As i have been posting since 2007, round up is not your Friend. A careful read of the science strongly supports that roundup is plausibly killing our frogs and reducing male fertility. By extension and not too far a stretch either, it must also be anticipated for bird die offs and a wide range of human ailments listed below.
Add in the Great Barrier reef and those massive new dead zones.
All of this is loudly blamed on someone else. Even climate change which is absurd. The pre Holocene climate had a 5 degree variation as against the present 2 degree variation. That might have driven something to extinction but did not worry the Great Barrier Reef.
.
The Real Reason Wheat is Toxic (it’s not the gluten)
Updated: February 20, 2017
The
stories became far too frequent to ignore. Emails from folks with
allergic or digestive issues to wheat in the United States experienced
no symptoms whatsoever when they tried eating pasta on vacation in
Italy.
Confused parents wondering why wheat consumption sometimes triggered
autoimmune reactions in their children but not at other times.
In my own home, I’ve long pondered why my husband can eat the wheat I prepare at home, but he experiences negative digestive effects eating even a single roll in a restaurant.
There is clearly something going on with wheat that is not well known
by the general public. It goes far and beyond organic versus
nonorganic, gluten or hybridization because even conventional wheat
triggers no symptoms for some who eat wheat in other parts of the world.
What indeed is going on with wheat?
For quite some time, I secretly harbored
the notion that wheat in the United States must, in fact, be
genetically modified. GMO wheat secretly invading the North American
food supply seemed the only thing that made sense and could account for
the varied experiences I was hearing about.
I reasoned that it couldn’t be the gluten or wheat hybridization.
Gluten and wheat hybrids have been consumed for thousands of years. It
just didn’t make sense that this could be the reason for so many people
suddenly having problems with wheat and gluten in general in the past
5-10 years.
Finally, the answer came over dinner a couple of months ago with a
friend who was well versed in the wheat production process. I started
researching the issue for myself, and was, quite frankly, horrified at
what I discovered.
The good news is that the reason wheat has become so toxic in the
United States is not because it is secretly GMO as I had feared (thank
goodness!).
The bad news is that the problem lies with the manner in which wheat is grown and harvested by conventional wheat farmers.
You’re going to want to sit down for this one. I’ve had some folks
burst into tears in horror when I passed along this information before.
Common wheat harvest protocol in
the United States is to drench the wheat fields with Roundup several
days before the combine harvesters work through the fields as the
practice allows for an earlier, easier and bigger harvest.
Pre-harvest application of the herbicide Roundup or other herbicides
containing the deadly active ingredient glyphosate to wheat and barley
as a desiccant was suggested as early as 1980. It has since become
routine over the past 15 years and is used as a drying agent 7-10 days
before harvest within the conventional farming community.
According to Dr. Stephanie Seneff of MIT who has studied the issue in depth
and who I recently saw present on the subject at a nutritional
Conference in Indianapolis, desiccating non-organic wheat crops with
glyphosate just before harvest came into vogue late in the 1990’s with
the result that most of the non-organic wheat in the United States is
now contaminated with it. Seneff explains that when you expose
wheat to a toxic chemical like glyphosate, it actually releases more
seeds resulting in a slightly greater yield: “It ‘goes to seed’ as it dies. At its last gasp, it releases the seed” says Dr. Seneff.
According to the US Department of Agriculture, as of 2012, 99% of
durum wheat, 97% of spring wheat, and 61% of winter wheat has been
treated with herbicides. This is an increase from 88% for durum wheat,
91% for spring wheat and 47% for winter wheat since 1998.
Here’s what wheat farmer Keith Lewis has to say about the practice:
I have been a wheat farmer for 50 yrs and one wheat production practice that is very common is applying the herbicide Roundup (glyposate) just prior to harvest. Roundup is licensed for preharvest weed control. Monsanto, the manufacturer of Roundup claims that application to plants at over 30% kernel moisture result in roundup uptake by the plant into the kernels. Farmers like this practice because Roundup kills the wheat plant allowing an earlier harvest.
A wheat field often ripens unevenly, thus applying Roundup preharvest evens up the greener parts of the field with the more mature. The result is on the less mature areas Roundup is translocated into the kernels and eventually harvested as such.
This practice is not licensed. Farmers mistakenly call it “desiccation.” Consumers eating products made from wheat flour are undoubtedly consuming minute amounts of Roundup. An interesting aside, malt barley which is made into beer is not acceptable in the marketplace if it has been sprayed with preharvest Roundup. Lentils and peas are not accepted in the market place if it was sprayed with preharvest roundup….. but wheat is ok.. This farming practice greatly concerns me and it should further concern consumers of wheat products.
Here’s what wheat farmer Seth Woodland of Woodland and Wheat in Idaho had to say about the practice of using herbicides for wheat dry down:
That practice is bad . I have fellow farmers around me that do it and it is sad. Lucky for you not all of us farm that way. Being the farmer and also the president of a business, we are proud to say that we do not use round up on our wheat ever!
This practice is not just widespread in the United States either. The
Food Standards Agency in the United Kingdom reports that use of Roundup
as a wheat desiccant results in glyphosate residues regularly showing
up in bread samples. Other European countries are waking up to to the
danger, however. In the Netherlands, use of Roundup is completely banned
with France likely soon to follow.
Using Roundup on wheat crops throughout the entire growing season and
even as a desiccant just prior to harvest may save the farmer money and
increase profits, but it is devastating to the health of the consumer
who ultimately consumes the glyphosate residue laden wheat kernels.
The chart below of skyrocketing applications of glyphosate to US
wheat crops since 1990 and the incidence of celiac disease is from a
December 2013 study published in the Journal Interdisciplinary Toxicology
examining glyphosate pathways to autoimmune disease. Remember that
wheat is not currently GMO or “Roundup Ready” meaning it is not
resistant to its withering effects like GMO corn or GMO soy, so
application of glyphosate to wheat would actually kill it.
While the herbicide industry maintains that glyphosate is minimally toxic to humans, research published in the Journal Entropy strongly argues otherwise by shedding light on exactly how glyphosate disrupts mammalian physiology.
Authored by Anthony Samsel and Stephanie Seneff of MIT, the paper
investigates glyphosate’s inhibition of cytochrome P450 (CYP) enzymes,
an overlooked component of lethal toxicity to mammals.
The currently accepted view is that ghyphosate is not harmful to
humans or any mammals. This flawed view is so pervasive in the
conventional farming community that Roundup salesmen have been known to
foolishly drink it during presentations!
However, just because Roundup doesn’t kill you immediately doesn’t
make it nontoxic. In fact, the active ingredient in Roundup lethally
disrupts the all important shikimate pathway found in beneficial gut
microbes which is responsible for synthesis of critical amino acids.
Friendly gut bacteria, also called probiotics, play a critical role
in human health. Gut bacteria aid digestion, prevent permeability of the
gastointestinal tract (which discourages the development of autoimmune
disease), synthesize vitamins and provide the foundation for robust
immunity. In essence:
Roundup significantly disrupts
the functioning of beneficial bacteria in the gut and contributes to
permeability of the intestinal wall and consequent expression of
autoimmune disease symptoms.
In synergy with disruption of the biosynthesis of important amino
acids via the shikimate pathway, glyphosate inhibits the cytochrome P450
(CYP) enzymes produced by the gut microbiome. CYP enzymes are critical
to human biology because they detoxify the multitude of foreign
chemical compounds, xenobiotics, that we are exposed to in our modern
environment today.
As a result, humans exposed to glyphosate through use of Roundup in
their community or through ingestion of its residues on industrialized
food products become even more vulnerable to the damaging effects of
other chemicals and environmental toxins they encounter!
What’s worse is that the negative impact of glyphosate exposure is
slow and insidious over months and years as inflammation gradually gains
a foothold in the cellular systems of the body.
The consequences of this systemic inflammation are most of the diseases and conditions associated with the Western lifestyle:
- Gastrointestinal disorders
- Obesity
- Diabetes
- Heart Disease
- Depression
- Autism
- Infertility
- Cancer
- Multiple Sclerosis
- Alzheimer’s disease
- And the list goes on and on and on …
In a nutshell, Dr. Seneff’s study
of Roundup’s ghastly glyphosate which the wheat crop in the United
States is doused with uncovers the manner in which this lethal toxin
harms the human body by decimating beneficial gut microbes with the
tragic end result of disease, degeneration, and widespread suffering.
Got the picture yet?
Even if you think you have no trouble digesting wheat, it is still
very wise to avoid conventional wheat as much as possible in your diet!
You Must Avoid Toxic Wheat No Matter What
The bottom line is that avoidance of conventional wheat in the United
States is absolutely imperative even if you don’t currently have a
gluten allergy or wheat sensitivity. The increase in the amount of
glyphosate applied to wheat closely correlates with the rise of celiac
disease and gluten intolerance.
Dr. Seneff points out that the increases
in these diseases are not just genetic in nature, but also have an
environmental cause as not all patient symptoms are alleviated by
eliminating gluten from the diet.
The effects of deadly glyphosate on your biology are so insidious that lack of symptoms today means literally nothing.
If you don’t have problems with wheat now, you will in the future if you keep eating conventionally produced, toxic wheat!
How to Eat Wheat Safely
Obviously, if you’ve already developed a sensitivity or allergy to wheat, you must avoid it. Period.
But, if you aren’t celiac or gluten sensitive and would like to
consume this ancestral food safely, you can do what we do in our home.
We source organic, naturally low in gluten, unhybridized Einkorn wheat for breadmaking, pancakes, cookies etc. Please note that einkorn is not to be confused with the more general term farro,
which includes emmer and spelt, which are both hybridized. You can
learn more about the scientific research on the “good” gluten in einkorn
in this article.
When we eat out or are purchasing food from the store, conventional
wheat products are rejected without exception. This despite the fact
that we have no gluten allergies whatsoever in our home – yet.
I am firmly convinced that if we did nothing, our entire family at
some point would develop sensitivity to wheat or autoimmune disease in
some form due to the toxic manner in which it is processed and the
glyphosate residues that are contained in conventional wheat products.
What Are You Going to Do About Toxic Wheat?
How did you react to the news that US wheat farmers are using
Roundup, not just to kill weeds, but to dry out the wheat plants to
allow for an earlier, easier and bigger harvest and that such a practice
causes absorption of toxic glyphosate, the active ingredient in Roundup
and other herbicides, right into the wheat kernels themselves?
Did you feel outraged and violated like I did? How will you implement
a conventional wheat-avoidance strategy going forward even if you
haven’t yet developed a problem with gluten or wheat sensitivity?
What about other crops where Roundup is used as a pre-harvest
dessicant such as barley, sugar cane, rice, seeds, dried beans and peas,
sugar cane, sweet potatoes, and sugar beets? Will you only be buying
these crops in organic form from now on to avoid this modern, man-made
scourge?
UPDATE: The Soil Association
in July 2015 called for an immediate ban on the use of glyphosate for
wheat ripening and desiccation purposes. The nonprofit reports that
glyphosate residues are widely found in nonorganic wheat samples and the
use of the herbicide on wheat crops has increased 400% in the past two
decades.
Dr. Robin Mesnage of the Department of Medical and Molecular Genetics
at Kings College in London, revealed new data analysis showing Roundup,
the most common brand of Glyphosate based herbicides, is 1,000 times
more toxic than genotoxic glyphosate alone due to the inclusion of other
toxic chemicals in its mix.
Peter Melchett, Soil Association policy director said; “If
Glyphosate ends up in bread it’s impossible for people to avoid it,
unless they are eating organic. On the other hand, farmers could easily
choose not to use Glyphosate as a spray on wheat crops – just before
they are harvested. This is why the Soil Association is calling for the
immediate ending of the use of Glyphosate sprays on wheat destined for
use in bread.”
Sarah, The Healthy Home Economist
Sources and More Information
Gluten Free Society Expert Interview Series
Presenting Dr. Seneff on Roundup:
I recently sat down with Dr. Seneff from MIT to discuss the potential dangers associated with exposure to the chemical glyphosate (also known as round up). This chemical is one of the most commonly used herbicides (weed killers) in the U.S. It is used primarily on genetically modified “Roundup Ready” crops like corn, soy, canola, sorghum, alfalfa, and cotton, but is also being used on sugar cane and coffee crops.To listen to the interview and get the in depth story from the source, click the link below.
Audio Player
Please
share, like, tweet, etc. Spread the word and together we can increase
awareness of this issue. You can read the transcript of the interview
below.
Always looking out for you,
Dr. O – The Gluten Free Warrior
Think you might be gluten sensitive? >>> Take this short quiz for free <<<
Transcript Part 1:
Dr. Osborne: Hi.
This is Dr. Peter Osborne with Gluten-free Society and today I have a
very special guest on the phone with me, Dr. Stephanie Seneff of MIT.
Dr. Seneff, thank you so much for being present today and taking the
time out of your busy schedule to speak with us.
Dr. Seneff: My pleasure. I’m delighted.
Dr. Osborne: Would you introduce yourself and just tell everyone what your background is and what your education is?
Dr. Seneff:
Yes. I’m at MIT. I’ve been here all my adult life. I went here as an
undergraduate, majored in biology with a minor in food and nutrition. My
PhD is in computer science and I’ve spent many years working in
computer science and I’ve spent many years working in computer science
natural language and understanding processing. Many papers published and
whatnot.
Over the past seven years, I’ve been transitioning more
to the biology side again, returning to the past, in a sense. I’ve
become really passionately interested in trying to understand what’s
causing all of the problems that we’re seeing today in our health. I’m
convinced that there are major environmental toxins that are making us
sick, and I need to identify which ones they are. I’ve been
systematically studying that for the last seven years and really gained a
lot of insight and understanding about what’s happening, and now the
question is how to fix it, I think.
I’ve published several papers
in the last few years in biology and medicine, with co-authors,
collaborated with a number of people in this space of the role of
environmental toxins in modern diseases.
Dr. Osborne:
Your recent paper, Interdisciplinary Toxicology, co-authored with
Anthony Sampsell, was what actually turned me on to some of your work
and theories around Roundup, the chemical that is prominently being used
on many of our crops. Can you talk a little bit about Roundup and talk
about its use and how that’s increased? Let’s go into how you found the
correlation between its use and the increased incidence of gluten
reactivity.
Dr. Seneff: It’s quite amazing. I mean,
when you start looking you see that among all the chemicals that are
used in growing our crops today, Roundup stands out as one whose usage
rates have gone up alarmingly in the last ten years, directly in step
with the alarming increase in a number of diseases, one of which is
Celiac Disease, which seems to have just appeared out of nowhere. I
don’t remember even knowing the word a few years back, and now you’ve
got the gluten free section in every grocery store in the country,
basically. It’s just come out of nowhere.
Interesting thing is
that wheat, of course wheat has been changed through the years. They’ve
done a lot of genetic modifications of the wheat. It’s not the same as
the heritage wheat was the in past, but I don’t think that’s the key
problem. The problem, I think, is that the glyphosate in Roundup,
glyphosate is the active ingredient in Roundup, is being sprayed on the
wheat increasingly right before the harvest.
Just a few days
before the harvest, they spray the wheat with Roundup intentionally, in
order to kill it. Wheat is not Roundup Ready. There are many crops that
are GMO modified to be Roundup Ready, meaning that they don’t die if
they’re exposed to this toxic chemical. Almost all plants die.
Glyphosate is a universal herbicide, which is why people find it
attractive, and it’s considered to be nontoxic, so farmers think it’s a
good choice.
Unfortunately, that is wrong. That is an incorrect
assumption, from what I’ve seen. I mean, the research that’s been done
already, there are a lot of papers that we’ve quoted and referenced in
our paper, showing that the idea that glyphosate is nontoxic is simply
not true.
We think the wheat gluten actually binds to the
glyphosate and that disrupts the process that usually happens in the
digestive system that would make it into a nontoxic form. That chemical
process gets disrupted by the glyphosate, and then the gluten becomes
something that the body becomes allergic to. That is what causes the
cascade that leads to celiac disease.
Dr. Osborne: What
you’re saying, then–I want to put it into very laymen’s terms for some
of our listeners–is that the glyphosate being sprayed on the wheat binds
to the wheat and basically increases its toxicity or makes it more
toxic. Or are you saying that the wheat–
Dr. Seneff: It makes it allergenic.
Dr. Osborne: Okay. It just basically makes it more allergenic.
Dr. Seneff: Yes
Dr. Osborne:
I’ve read some papers, and some of the things you’ve mentioned in your
research are the effect on transglutaminases. I’ve read some papers on
adding microbial transglutaminases to dairy products and how that
increases the allergenicity of dairy, because it unfolds proteins in the
dairy that actually look very similar to gluten and therefore increase
that reaction.
Dr. Seneff: That’s very interesting. I didn’t know that, actually. That’s something new to me. I guess–
Dr. Osborne: I’ll have to send you that.
Glyphosate and Gluten Part 2
Dr. Seneff: Yes, I would love to see that. Another interesting thing that directly connects to glyphosate: Glyphosate kills bacteria,
and it preferentially kills the good bacteria in your gut. One of those
is bifido bacteria, and those guys are really important for processing
the wheat, the gluten. When they’re destroyed by glyphosate, then the
wheat suffers not being fully digested properly, such that it remains in
the allergenic forms in your gut and causes this reaction. The fact
that glyphosate kills these bacteria is another feature that’s going to
lead to celiac disease.
Dr. Osborne: We have a function
basically on the normal microbiome within the gut wall, that it has
antibiotic-based effect on preferential bacteria that aid in the
digestion of difficult to digest proteins. Have you seen the new
research that’s come out on sourdough bread, adding high levels of lactobacillus?
Dr. Seneff:
Yes, that’s another one, lactobacillus, that’s also preferentially
killed by glyphosate. Glyphosate kills the ones that you need to be able
to properly process these foods.
Dr. Osborne: We have an
effect on gut bacteria. Then we have the fact that it makes food that
is sprayed with the chemical more allergenic. In essence, people react
or respond even more aggressively to them than they otherwise would.
What are some of the other effects that glyphosate has on the human
body, or on the plant, that affects the human as they eat it?
Dr. Seneff:
That’s right, because the argument is that glyphosate disrupts this
critical pathway in plants, called the shikimate pathway. That pathway
produces three essential amino acids, which are called aromatic amino
acids: tryptophan, tyrosine, and phenylalanine.
It turns out,
these three amino acids are really important to our health and we depend
on our food and our bacteria to produce them for us. The food that is
exposed to glyphosate is depleted in these nutrients. The gut bacteria
can’t produce them in the context of glyphosate, so we end up deficient
in these nutrients, and one of the big ones is tryptophan.
Tryptophan
is the sole precursor to serotonin, and serotonin deficiency is a huge
problem in the modern world. It’s linked to depression, violent
behavior, obesity, and celiac disease. I think serotonin deficiency is a
critical piece of the puzzle, as well.
Dr. Osborne: No doubt. You said tyrosine, as well?
Dr. Seneff: Yes.
Dr. Osborne:
We have tryptophan and tyrosine, so serotonin, as well as tyrosine
being a precursor for thyroid hormone. I know in my clinic, that is one
of the most prolific problems. Patients will come in and they will have
hypothyroidism or will have developed Hashimoto’s disease.
Dr. Seneff: Right.
Dr. Osborne:
What you’re saying about glyphosate is that it can cause deficiency in
the actual amino acids in the food that we eat, because the plants need
to be able to synthesize those foods to survive and glyphosate inhibits
that process. What you’re also saying is that glyphosate destroys and
damages our gut flora which helps us to digest the food and produce
these amino acids, so there are two mechanisms of action here that are
causing that deficiency?
Dr. Seneff: Yes. You’re good. Great summary.
Dr. Osborne:
Big problems, right? I know one of the things in our clinic that we use
or that we measure, oftentimes we’ll measure serotonin and oftentimes
we’ll also try to measure thyroid hormone, and this is very prolific,
we’ll see these numbers coming back. I know if we look at even the top
five drugs in the United States, one of the top in that is
antidepressants.
Dr. Seneff: Right.
Dr. Osborne:
Now, let me hear your thoughts on serotonin’s impact on gut motility.
We have a gut nervous system and its primary neurotransmitter is
serotonin. Can you comment a little bit more on that?
Dr. Seneff:
Well, yes. Actually, what I think happens, and this is speculation. We
didn’t find papers that said this, but we could see the evidence from
the details in the research–that the serotonin producers in association
with celiac disease are very aggressive to make serotonin, whenever they
have a chance. I think it’s because of the tryptophan deficiency.
As
soon as you eat some food that has tryptophan in it, your cells in your
gut that make serotonin grab the opportunity to make it, and they make
too much, and then you get things like nausea and diarrhea. It gives you
the gut mobility. It overdoes it. It’s because your body is so
desperate for serotonin that the moment it gets the opportunity, it has
to overdo it to take advantage of that opportunity, because it’s so
scarce and it needs it so badly.
I think there’s sort of a
swinging back and forth between too little and too much. It ends up with
diarrhea and constipation, depending on the diet, because you just
aren’t getting a steady supply.
Dr. Osborne: Great point.
We get kind of a transient up and down effect based on what the diet is
giving, because the gut is in a state of deficit.
Dr. Seneff: Oversensitivity because of the deficit.
Dr. Osborne: Right. Then it needs to be able to produce, so when it gets the opportunity it makes an abundance.
Dr. Seneff: Too much. Yes.
Dr. Osborne: One of the things I read about in your paper was the cytochrome P450, which is the enzymatic systems within the liver that help the body detoxify. Can you tell us the effect that glyphosate has on those particular systems?
Dr. Seneff:
Yes. That is a huge piece of the puzzle, and were really astonished as
we looked at how many different aspects of celiac disease were
connected. Celiac disease is a very complex disease with a lot of
interesting comorbidities. What’s amazing is that so many of them can be
explained simply by the cytochrome P450 enzymes, which you can call CYP
enzymes for short.
They’re amazing. There are so many of them in
the liver, and they do so many different things, and all of the things
that they do are disrupted in celiac disease. It’s really perfect.
Glyphosate disrupts those enzymes, that’s been shown in rat liver. In
the liver of a mammal, glyphosate interferes with the cytochrome P450
enzymes.
For example, a simple example, is that they activate
vitamin D. When you measure vitamin D, you’re measuring the form that’s
been activated by the liver using a CYP enzyme. I’m sure that you’ve
been hearing, all of a sudden we have a massive vitamin D deficiency
problem in this country, so the solution is just to pump everyone full
of vitamin D supplements. The problem is due to, I believe, the fact
that glyphosate is preventing the vitamin D from getting activated,
which is why it’s low, and it’s low in association with celiac disease.
It’s that simple.
Dr. Osborne: Okay. It actually inhibits the activation of vitamin D metabolites that go about to bring about hormonal functions for vitamin D.
Glyphosate, pathways to modern diseases II: Celiac sprue and gluten intolerance
2
This article has been cited by other articles in PMC.
Celiac
disease, and, more generally, gluten intolerance, is a growing problem
worldwide, but especially in North America and Europe, where an
estimated 5% of the population now suffers from it. Symptoms include
nausea, diarrhea, skin rashes, macrocytic anemia and depression. It is a
multifactorial disease associated with numerous nutritional
deficiencies as well as reproductive issues and increased risk to
thyroid disease, kidney failure and cancer. Here, we propose that
glyphosate, the active ingredient in the herbicide, Roundup®,
is the most important causal factor in this epidemic. Fish exposed to
glyphosate develop digestive problems that are reminiscent of celiac
disease. Celiac disease is associated with imbalances in gut bacteria
that can be fully explained by the known effects of glyphosate on gut
bacteria. Characteristics of celiac disease point to impairment in many
cytochrome P450 enzymes, which are involved with detoxifying
environmental toxins, activating vitamin D3, catabolizing vitamin A, and
maintaining bile acid production and sulfate supplies to the gut.
Glyphosate is known to inhibit cytochrome P450 enzymes. Deficiencies in
iron, cobalt, molybdenum, copper and other rare metals associated with
celiac disease can be attributed to glyphosate's strong ability to
chelate these elements. Deficiencies in tryptophan, tyrosine, methionine
and selenomethionine associated with celiac disease match glyphosate's
known depletion of these amino acids. Celiac disease patients have an
increased risk to non-Hodgkin's lymphoma, which has also been implicated
in glyphosate exposure. Reproductive issues associated with celiac
disease, such as infertility, miscarriages, and birth defects, can also
be explained by glyphosate. Glyphosate residues in wheat and other crops
are likely increasing recently due to the growing practice of crop
desiccation just prior to the harvest. We argue that the practice of
“ripening” sugar cane with glyphosate may explain the recent surge in
kidney failure among agricultural workers in Central America. We
conclude with a plea to governments to reconsider policies regarding the
safety of glyphosate residues in foods.
Keywords: celiac disease, gluten, glyphosate, food, cytochrome P450, deficiency
1 Introduction
Gluten
intolerance is a growing epidemic in the U.S. and, increasingly,
worldwide. Celiac sprue is a more specific disorder, characterized by
gluten intolerance along with autoantibodies to the protein,
transglutaminase, which builds crosslinks in undigested fragments of
gliadin, a major constituent of gluten (Green & Cellier, 2007).
The autoantibodies are produced as an immune response to undegraded
fragments of proteins in gluten. A remarkable set of symptoms develop
over time in association with celiac disease, including weight loss,
diarrhea, chronic fatigue, neurological disorders, anemia, nausea, skin
rashes, depression, and nutrient deficiencies. Usually, but not always, a
strict gluten-free diet can alleviate many of the symptoms. A key
associated pathology is an inflammatory response in the upper small
intestine, leading to villous atrophy, a flattening of the microvilli
which impairs their ability to function in their important role in
absorbing nutrients.
Some have suggested that the recent
surge in celiac disease is simply due to better diagnostic tools.
However, a recent study tested frozen sera obtained between 1948 and
1954 for antibodies to gluten, and compared the results with sera
obtained from a matched sample from people living today (Rubio-Topia et al., 2009).
They identified a four-fold increase in the incidence of celiac disease
in the newer cohort compared to the older one. They also determined
that undiagnosed celiac disease is associated with a 4-fold increased
risk of death, mostly due to increased cancer risk. They concluded that
the prevalence of undiagnosed celiac disease has increased dramatically
in the United States during the past 50 years.
Transglutaminases
play many important roles in the body, as they form covalent crosslinks
in complex proteins in connection with blood coagulation, skin-barrier
formation, extracellular matrix assembly, and fertilization, endowing
the substrate with protection from degradation by proteases (Lorand
& Graham, 2003).
They also form crosslinks in undigested fragments of gliadin derived
from wheat, and sensitivity to certain of these fragments leads to the
development of autoantibodies to tissue transglutaminase (Esposito et al., 2002) that inhibit its activity.
Glyphosate
is the active ingredient in the herbicide Roundup. It is a
broad-spectrum herbicide, considered to be nearly nontoxic to humans
(Williams et al., 2000). However, a recent paper (Samsel & Seneff, 2013),
argued that glyphosate may be a key contributor to the obesity epidemic
and the autism epidemic in the United States, as well as to several
other diseases and conditions, such as Alzheimer's disease, Parkinson's
disease, infertility, depression, and cancer. Glyphosate suppresses
5-enolpyruvylshikimic acid-3-phosphate synthase (EPSP synthase), the
rate-limiting step in the synthesis of the aromatic amino acids,
tryptophan, tyrosine, and phenylalanine, in the shikimate pathway of
bacteria, archaea and plants (de MarÃa et al., 1996). In plants, aromatic amino acids collectively represent up to 35% of the plant dry mass (Franz, 1997).
This mode of action is unique to glyphosate among all emergent
herbicides. Humans do not possess this pathway, and therefore we depend
upon our ingested food and our gut microbes to provide these essential
nutrients. Glyphosate, patented as an antimicrobial (Monsanto Technology
LLC, 2010),
has been shown to disrupt gut bacteria in animals, preferentially
killing beneficial forms and causing an overgrowth of pathogens. Two
other properties of glyphosate also negatively impact human health –
chelation of minerals such as iron and cobalt, and interference with
cytochrome P450 (CYP) enzymes, which play many important roles in the
body. We will have much more to say about these aspects in later
sections of this paper.
A recent study on glyphosate
exposure in carnivorous fish revealed remarkable adverse effects
throughout the digestive system (Senapati et al., 2009).
The activity of protease, lipase, and amylase were all decreased in the
esophagus, stomach, and intestine of these fish following exposure to
glyphosate. The authors also observed “disruption of mucosal folds and
disarray of microvilli structure” in the intestinal wall, along with an
exaggerated secretion of mucin throughout the alimentary tract. These
features are highly reminiscent of celiac disease. Gluten peptides in
wheat are hydrophobic and therefore resistant to degradation by gastric,
pancreatic and intestinal proteases (Hershko & Patz, 2008).
Thus, the evidence from this effect on fish suggests that glyphosate
may interfere with the breakdown of complex proteins in the human
stomach, leaving larger fragments of wheat in the human gut that will
then trigger an autoimmune response, leading to the defects in the
lining of the small intestine that are characteristic of these fish
exposed to glyphosate and of celiac patients. As illustrated in Figure 1,
the usage of glyphosate on wheat in the U.S. has risen sharply in the
last decade, in step with the sharp rise in the incidence of Celiac
disease. We explain the reasons for increased application of glyphosate
to wheat in Section 13.
Hospital discharge diagnosis (any) of celiac disease ICD-9 579 and glyphosate applications to wheat (R=0.9759, p≤1.862e-06). Sources: USDA:NASS; CDC. (Figure courtesy of Nancy Swanson).
In
the remainder of this paper, we will first show that gut dysbiosis,
brought on by exposure to glyphosate, plays a crucial role in the
development of celiac disease. Many CYP enzymes are impaired in
association with celiac disease, and we show that glyphosate's known
suppression of CYP enzyme activity in plants and animals plausibly
explains this effect in humans. In Section 4, we describe the role of
excess retinoic acid in celiac disease, and show how this ties also to
reproductive problems. We link this to the known effects of glyphosate
on retinoic acid, mediated by its suppression of CYP enzymes. Section 5
addresses cobalamin deficiency, a known pathology associated with celiac
disease that leads to macrocytic anemia. We argue that this follows as a
direct consequence of glyphosate's ability to chelate cobalt. Section 6
discusses in more depth the role of anemia in celiac disease, a
consequence of both cobalamin and iron deficiency. Section 7 discusses
molybdenum deficiency and its link to microcephaly, which is associated
with celiac disease. Section 8 discusses the link between selenium
deficiency and autoimmune thyroid disease. Section 9 discusses kidney
disease in connection with celiac disease and glyphosate. Section 10
discusses various nutritional deficiencies associated with celiac
disease, and shows how these can directly be explained by glyphosate.
Section 11 discusses the link between celiac disease and certain rare
cancers that have also been linked to glyphosate. Section 12 goes into
an in-depth discussion of how glyphosate might promote autoantibodies to
transglutaminase. Following a section which presents compelling
evidence that glyphosate residues in wheat, sugar and other crops are
likely increasing in recent decades, and a section discussing the
increased risk to kidney failure in agricultural workers exposed to
excess glyphosate occupationally, we close with a discussion section
that summarizes our findings, and a conclusion which implores
governments to pay more attention to the damaging consequences of the
escalation in chemical warfare on weeds that characterizes current
agricultural practices.
2 Gut bacteria
In
this section, we first discuss the role of pathogens in inducing the
breakdown of tight junctions in enterocytes lining the small intestinal
wall. We then show that glyphosate is associated with an overgrowth of
pathogens along with an inflammatory bowel disease in animal models. A
parallel exists with celiac disease where the bacteria that are
positively and negatively affected by glyphosate are overgrown or
underrepresented respectively in association with celiac disease in
humans. We also discuss how the beneficial bacteria that are negatively
impacted by glyphosate can protect from celiac disease through their
enzymatic activities on gluten, and point to several articles
recommending treatment plans based on probiotics.
Pathogens,
through their activation of a potent signaling molecule called zonulin,
induce a breakdown of the tight junctions in cells lining the gut,
leading to “leaky gut” syndrome (Fasano, 2011). Concentrations of zonulin were sharply elevated (p<0.000001) in subjects with celiac disease during the acute phase (Fasano et al., 2000).
As many as 30% of celiac patients continue to experience GI symptoms
after adopting a gluten-free diet, despite optimal adherence, a
condition that was attributed to bacterial overgrowth in the small
intestine (Tursi et al., 2003). Figure 2 shows that there is a correlation between glyphosate application to wheat and the incidence of intestinal infections.
Deaths due to intestinal infections ICD A04, A09; 008, 009 with glyphosate applications to wheat (R=0.9834, p≤3.975e-09). Sources: USDA:NASS; CDC. (Figure courtesy of Nancy Swanson).
Evidence of disruption of gut bacteria by glyphosate is available for poultry (Shehata et al., 2013), cattle (Krüger et al., 2013), and swine (Carman et al., 2013). Glyphosate disrupts the balance of gut bacteria in poultry (Shehata et al., 2013),
increasing the ratio of pathogenic bacteria to other commensal
microbes. Salmonella and Clostridium are highly resistant to glyphosate,
whereas Enterococcus, Bifidobacteria, and Lactobacillus are especially
susceptible. Glyphosate was proposed as a possible factor in the
increased risk to Clostridium botulinum infection in cattle in Germany
over the past ten to fifteen years (Krüger et al., 2013b).
Pigs fed GMO corn and soy developed widespread intestinal inflammation
that may have been due in part to glyphosate exposure (Carman et al., 2013).
Celiac
disease is associated with reduced levels of Enterococcus,
Bifidobacteria and Lactobacillus in the gut and an overgrowth of
pathogenic gram negative bacteria (Sanz et al., 2011; Di Cagno et al., 2011; Collado et al., 2007). In (Di Cagno et al., 2011),
Lactobacillus, Enterococcus and Bifidobacteria were found to be
significantly lower in fecal samples of children with celiac disease
compared to controls, while levels of the pathogens, Bacteroides,
Staphylococcus, Salmonella, a Shighella were elevated. In (Collado et al., 2007),
another study comparing the fecal material of celiac infants to healthy
controls, Bacteroides, Clostridium and Staphylococcus were all found to
be significantly higher (p<0.05). Sulfate-reducing bacterial counts were also elevated (p<0.05) (Nadal et al., 2007; Collado et al., 2007),
an interesting observation which we will return to later in this paper.
A significant reduction in Bifidobacteria was also found in (Nadal et al., 2007).
An increased excretion of the bacterial metabolites p-Cresol and phenol
has also been recognized in association with celiac disease (Tamm, 1984).
p-Cresol is produced via anaerobic metabolism of tyrosine by pathogenic
bacteria such as Clostridium difficile (D'Ari and Barker, 1985).
It is a highly toxic carcinogen, which also causes adverse effects on
the central nervous system, the cardiovascular system, lungs, kidney and
liver (Kelly et al., 1994).
Probiotic
treatments are recommended to aid in digestive healing in celiac
disease. The proteolytic activity of Lactobacilli aids the breakdown of
wheat into less allergenic forms. Ongoing research aims to produce
gluten-containing sourdough breads fermented by Lactobacilli that can
then serve as probiotics to help ameliorate the symptoms of celiac
disease and allow celiac patients to consume wheat (Gobbetti et al., 2007).
Probiotic Lactobacilli produce the enzyme phytase which breaks down
phytates that would otherwise deplete important minerals and other
cations through chelation (Famularo et al., 2005). Their activities would therefore improve absorption of these micronutrients, a known problem in celiac patients (Cavallaro et al., 2004). Glyphosate itself also chelates rare minerals, a subject we will address in the section on nutritional deficiencies.
Probiotic treatment with Bifidobacteria has been shown to alleviate symptoms associated with celiac disease (Smecuol et al., 2013; Whorwell et al., 2006). Bifidobacteria suppress the pro-inflammatory milieu triggered by the microbiota of celiac patients (Medina et al., 2008).
Live cultures of Bifidobacterium lactis would promote healing of the
gut if offered as treatment in conjunction with the gluten-free diet, or
might even allow the celiac patient to consume modest amounts of gluten
without damaging effects (Lindfors et al., 2008).
In this in vitro study, it was demonstrated that B. lactis reduced
epithelial permeability and improved the integrity of the tight
junctions in human colon cells.
In
summary, celiac disease is associated with a reduced presence in the gut
of commensal bacteria such as Lactobacilli and Bifidobacteria, which
are known to be preferentially killed by glyphosate, and with an
overabundance of C. difficile, which is known to be promoted by
glyphosate exposure. Bifidobacteria and Lactobacilli are both capable of
modifying gluten in such a way as to make it less allergenic, a feature
that is being exploited in recent efforts to develop gluten-containing
foods that may be safe for consumption by celiac patients. Probiotics
containing live forms of these bacteria are also being actively marketed
today.
3 CYP Enzyme impairment and sulfate depletion
As mentioned previously, glyphosate has been shown to suppress CYP enzymes in plants (Lamb et al., 1998) and animals (Hietanen et al., 1983).
A study on rats demonstrated that glyphosate decreased the levels of
CYP enzymes and monooxygenase activities in the liver and the intestinal
activity of aryl hydrocarbon hydroxylase (Hietanen et al., 1983).
CYP enzymes are essential for detoxification of many compounds in the liver (Lindros, 1997).
Intraperitoneal exposure of rats to Roundup in acute doses over a short
time interval induced irreversible damage to hepatocytes and elevated
urinary markers of kidney disease. This was associated with lipid
peroxidation and elevated levels of the inflammatory cytokine tumor
necrosis factor (TNF-α) (El-Shenawy, 2009).
CYP3A is constitutively expressed in human intestinal villi and plays
an important role in drug metabolism (Cupp & Tracy, 1998). Celiac disease is associated with a decrease in the intestinal CYP3A (Lang et al., 1996). This defect is restored by a gluten free diet.
Impaired gallbladder bile acid production (Colombato et al., 1977) and biliary cirrhosis, an inflammatory liver disease characterized by obstruction of the bile duct (Dickey et al., 1997), have been shown to co-occur with celiac disease. CYP enzymes are crucial in the production of bile acids (Lorbek et al., 2012).
An obligatory CYP enzyme in bile acid synthesis, CYP27A, has been
identified as being identical to the mitochondrial vitamin D3 activating
enzyme (Wikvall, 2001). In (Kemppainen et al., 1999),
64% of men and 71% of women with celiac disease were found to be
vitamin D3 deficient, manifested as low spinal bone mineral density.
Celiac disease is associated with impaired gall bladder function and
decreased pancreatic secretions (Brown et al., 1987; Benini et al., 2012) along with recurrent pancreatitis (Patel et al., 1999). Abnormalities in bile acid secretion have been found in children suffering from celiac disease (Ejderhamn et al., 1992). Celiac patients exhibit abnormally low synthesis of cholecystokinin (Deprez et al., 2002),
but it has also become apparent that the gall bladder is less
responsive to stimulation of contraction by cholecystokinin (Brown et al., 1987).
A reversible defect of gallbladder emptying and cholecystokinin release
has been identified in association with celiac disease (Maton et al., 1985). These pathologies may be related to impaired CYP enzyme activity induced by glyphosate.
While
it is clear that CYP enzymes play an important role in bile acid
synthesis and in cholesterol homeostasis, the details have not yet been
worked out (Lorbek et al., 2012).
However, some mouse knockout experiments produce embryonically lethal
effects, pointing to the importance of these enzymes to biological
systems. Disruption of Cyp7A1, involved in bile acid synthesis in mice,
induces elevated serum cholesterol and early death.
A
link has been established between celiac disease and non-alcoholic fatty
liver, which is likely due to the liver's inability to export
cholesterol sulfate through the bile acids due to impaired CYP enzymes
(Lorbek et al., 2012).
This requires a private store of fats to house the excess cholesterol
that cannot be exported in bile. This would also likely lead to
insufficient sulfate supplies to the small intestine, and could result
in impaired heparan sulfate synthesis in the glycosaminoglycans and
subsequent pathologies. Heparan sulfate populating the
glycosaminoglycans (GAGs) surrounding enterocytes is essential for the
proper functioning of the small intestines. Leakage of both albumin and
water in both the vasculature and tissues results when the negative
charge is reduced due to insufficient sulfation of the polysaccharide
units (Sunergren et al., 1987). Vascular leakage may be a consequence of degradation of sulfated GAGs due to inflammatory agents (Klein et al., 1992). A similar problem may occur in the kidneys leading to albumin loss into urine during nephrosis (Vernier et al., 1983).
Intestinal protein loss in inflammatory enteropathy associated with
celiac disease may also be due to a deficiency in the sulfated GAGs
(Murch et al., 1993; Murch, 1995).
A case study of three infants with congenital absence of enterocyte
heparan sulfate demonstrated profound enteric protein loss with
secretory diarrhoea and absorption failure, even though their intestines
were not inflamed (Murch et al., 1996).
In (Samsel and Seneff, 2013),
a hypothesis was developed that glyphosate disrupts the transport of
sulfate from the gut to the liver and pancreas, due to its competition
as a similarly kosmotropic solute that also increases blood viscosity.
(Kosmotropes are ions that induce “structure ordering” and “salting out”
of suspended particles in colloids). Insufficient sulfate supply to the
liver is a simple explanation for reduced bile acid production. The
problem is compounded by impaired CYP enzymatic action and impaired
cycling of bile acids through defective enterocytes in the upper small
intestine. The catastrophic effect of loss of bile acids to the feces
due to impaired reuptake compels the liver to adopt a conservative
approach of significantly reduced bile acid synthesis, which, in turn,
leads to gall bladder disease.
The protein, Nuclear
factor κ-lightchain-enhancer of activated B cells (NF-κB) controls DNA
transcription of hundreds of genes and is a key regulator of the immune
response to infection (Tieri et al., 2012).
Light chains are polypeptide subunits of immunoglobulins. NF-κB
responds to stimulation from bacterial and viral antigens, inflammatory
cytokines like TNF-α, free radicals, oxidized LDL, DNA damage and UV
light. The incidence of acute pancreatitis has been increasing in recent
years (Bhatia, 2012),
and it often follows billiary disease. A local inflammatory reaction at
the site of injury coincides with an increase in the synthesis of
hydrogen sulfide (H2S) gas. H2S regulates the
inflammatory response by exciting the extracellular signal regulated
(ERK) pathway, leading to production of NF-κB (Bhatia, 2012). We hypothesize that H2S,
while toxic, is a source of both energy and sulfate for the pancreas,
derived from sulfur-containing amino acids such as cysteine and
homocysteine. Dehydroepiandrosterone (DHEA) sulfate, but not DHEA,
inhibits NF-κB synthesis, suggesting that sulfate deficiency is a driver
of inflammation (Iwasaki et al., 2004).
While H2S
is well known as a toxic gas through its inhibition of aerobic
respiration, a recent paradigm shift in the research surrounding H2S has been inspired by the realization that it is an important signaling gas in the vasculature, on par with nitric oxide (Li et al., 2011). H2S can serve as an inorganic source of energy to mammalian cells (Módis et al., 2013). 3-mercaptopyruvate sulfurtransferae (3MST) is expressed in the vascular endothelium, and it produces H2S from mercaptopyruvate, an intermediary in the breakdown of cysteine (Kimura, 2011). Endogenously produced H2S derived from 3-mercaptopyruvate stimulates additional mitochondrial H2S production, which then is oxidized to thiosulfate via at least three different pathways (Ingenbleek and Kimura, 2013; Hildebrandt and Grieshaber, 2008; Goubern et al., 2007), producing ATP. The inflammatory agent superoxide can act as substrate for the oxidation of H2S to sulfite and subsequently sulfate and the activated form, PAPS (Seneff et al., 2012),
but will likely induce oxidative damage in the pancreas, particularly,
as we will see in section 7, if molybdenum deficiency impairs
sulfite-to-sulfate synthesis.
Pancreatic beta cells express extraordinarily high levels of heparan sulfate, which is essential for their survival (Ziolkowski et al., 2012),
since it protects them from ROS-induced cell death. Because sulfate
transport via the hepatic portal vein is likely disrupted by glyphosate,
H2S, whether derived from sulfur-containing amino acids or
supplied via diffusion following its production by sulfur-reducing
bacteria in the gut, can become an important source of sulfur for
subsequent sulfate production locally in the pancreatic cells.
Pancreatic elastase is a serine protease that is needed to assist in
protein degradation, but an overabundance can lead to autolysis of
tissues (Ito et al., 1998). Cholesterol sulfate inhibits pancreatic elastase (Ito et al., 1998),
so a deficiency in cholesterol sulfate supply due to impaired sulfate
supply to the liver and impaired CYP function should increase the risk
of tissue digestion by pancreatic enzymes, contributing to the loss of
villi in the upper small intestine observed in celiac disease.
In
the early 1990's a newly recognized disease began to appear,
characterized by eosinophil infiltration into the esophagus, which
manifested as dysphagia in adults and refractory reflux symptoms in
children (Lucendo & Sánchez-Cazalilla, 2012).
This disease, termed eosinophilic esophagitis (EOE), is associated with
a Th2 immune profile and synthesis of the cytokine IL-13, which has
direct cytotoxic effects on epithelial cells. A dose-dependent induction
of eosinophilia by intratracheal delivery of IL-13 confirms its
association with EOE (Mishra and Rothenberg, 2003). An association has been found between EOE and celiac disease (Leslie et al., 2010).
Patients with refractory celiac disease that is not corrected by
dietary gluten restriction show an increased production of IL-13 in the
gut (Gross et al., 2013). The incidence of EOE has increased at alarming rates in Western countries in the last three decades (Furuta et al., 2007; Liacouras et al., 2011; Prasad et al., 2009).
Glyphosate
is highly corrosive to the esophageal epidermal lining, with upper GI
tract injury observed in 94% of patients following glyphosate ingestion
(Chang et al., 1999). In (Zouaoui et al., 2013),
the most common symptoms in an acute response from glyphosate poisoning
were oropharyngeal ulceration, nausea and vomiting. We hypothesize that
glyphosate induces EOE via a systemic response as well as through
direct contact. The pathogenesis of EOE is related to food
sensitivities, but airborne exposure to chemicals in the lungs can also
induce it, so it does not require physical contact to the allergen
(Blanchard & Rothenberg, 2008). It is conceivable that glyphosate is responsible for the emergence of EOE.
The
cytochrome P450 reductase (CPR) and cytochrome P450 (CP) enzyme system
is essential for inducing nitric oxide release from organic nitrates
(Li, 2006).
The nitrate moiety is reduced while simultaneously oxidizing NADPH to
NADP+. This system is invoked in organic nitrate drug treatment for
cardiovascular therapy. The reaction depends on anaerobic, acidic
conditions, a feature of venous rather than arterial blood. Since
L-arginine is substrate for NO synthesis by endothelial nitric oxide
synthase (eNOS) under oxidative conditions (Förstermann and Münze, 2006), it is likely that CPR and CP play an important role mainly in stimulating venous
smooth muscle relaxation. Impaired venous relaxation would likely
contribute to venous thrombosis, which is a well-established
complication of celiac disease (Zenjari et al., 1995; Marteau et al., 1994, Grigg, 1999, Halfdanarson et al., 2007).
In
summary, celiac disease is associated with multiple pathologies in the
digestive system, including impaired gall bladder function, fatty liver,
pancreatitis, and EOE. We have argued here that many of these problems
can be traced to impaired CYP function in the liver due to glyphosate
exposure, leading to insufficient flow of bile acids through the
circular pathway between the liver and the gut. This results in a
system-wide depletion in sulfate, which induces inflammation in multiple
organs to produce sulfate locally. A potential sulfur source for
sulfate synthesis could be hydrogen sulfide gas, provided in part by the
local breakdown of sulfur-containing amino acids like cysteine and
homocysteine and in part by diffusion of the gas produced from inorganic
dietary sources by sulfur-reducing bacteria in the large intestine.
Impaired CYP enzyme function may also contribute to venous thrombosis,
for which celiac disease is an established risk factor.
4 Retinoic acid, celiac disease and reproductive issues
In
this section, we first establish that excess retinoic acid (RA) is a
risk factor for celiac disease. We then show that excess RA leads to
complications in pregnancy and teratogenic effects in offspring.
Glyphosate has been shown to exhibit teratogenic effects in line with
known consequences of excess RA exposure to the embryo, and we propose
that the mechanism for this effect may be glyphosate's known disruption
of CYP enzymes (Samsel & Seneff, 2013),
which are involved in RA catabolism. This then links glyphosate to
increased risk to celiac disease via its direct effects on RA. And it
identifies a possibly important factor in the association of celiac
disease with reproductive issues. We also discuss other adverse effects
of excess retinoic acid and a possible relationship to impaired sulfate
supply to the gut.
In celiac disease, T cells develop antibody responses against dietary gluten, a protein present in wheat (Jabri & Sollid, 2009).
RA, a metabolite of vitamin A, has been shown to play a critical role
in the induction of intestinal regulatory responses (Mora et al., 2008; Coombes et al., 2007; Mucida et al., 2007).
The peptide in gluten, A-gliadin p31-43, induces interleukin 15
(IL-15), a key cytokine promoting T-cell activation (Hershko & Patz,
2008). RA synergizes with high levels of IL-15 to promote JNK phosphorylation (Nanda, 2011; DePaolo et al., 2011), which potentiates cellular apoptosis (Putcha et al., 2003).
IL-15 is a causative factor driving the differentiation of precursor
cells into anti-gluten CD4+ and CD8+ Th1 cells in the intestinal mucosa.
Furthermore, in (DePaolo et al., 2011),
it was discovered that RA exhibits an unanticipated co-adjuvant
property to induce Th1 immunity to antigens during infection of the
intestinal mucosa with pathogens. Retinoic acid has also been shown to
directly suppress transglutaminase activity, another way in which it
would negatively impact celiac disease (Thacher et al., 1985).
Thus, it is becoming clear that excess exposure to RA would increase
risk to celiac disease, and warnings have been issued regarding
potential adverse effects of RA supplements on celiac disease.
It
is well established that high RA levels leads to teratogenic effects
both in human and experimental models. Brain abnormalities such as
microcephaly, impairment of hindbrain development, mandibular and
midfacial underdevelopment, and cleft palate are all implicated (Sulik et al., 1988; Clotman et al., 1998).
Women with celiac disease are known to have higher rates of
infertility, miscarriages, and birth defects in their offspring
(Freeman, 2010; Martinelli et al., 2000; Dickey et al., 1996; Collin et al., 1996). Excess RA could be a significant factor in these complications.
A
possible mechanism by which glyphosate might induce excess RA is via
its interference with the CYP enzymes that metabolize RA. There are at
least three known CYPs (CYP26A1, CYP26B1 and CYP26C1) that catabolize
RA, and they are active in both the embryo and the adult (Taimi et al., 2004).
A 1/5000 dilution of glyphosate was sufficient to induce reproducible
malformations characteristic of RA exposure in frog embryos (Paganelli et al., 2010).
Pathologies included shortening of the trunk, reduction in the size of
the head, abnormally small eyes or the presence of only one eye
(cyclopia), and other craniofacial malformations in the tadpole.
Glyphosate's toxicity to tadpoles has been well demonstrated, as it
killed nearly 100% of larval amphibians exposed in experimental outdoor
pond mesocosms (Relyea, 2005).
According
to official records, there has been a recent 4-fold increase in
developmental malformations in the province of Chaco, Argentina, where
glyphosate is used massively on GMO monocrops of soybeans (Carrasco, 2013).
In Paraguay, 52 cases of malformations were reported in the offspring
of women exposed during pregnancy to agrochemicals, including
anencephaly, microcephaly, facial defects, cleft palate, ear
malformations, polydactily, and syndactily (BenÃtez-Leite et al., 2009).
In in vitro studies on human cell lines, DNA strand breaks, plasma
membrane damage and apoptosis were observed following exposure to
glyphosate-based herbicides (Gasnier et al., 2009).
Another factor in teratogenetic effects of glyphosate may be the
suppression of the activity of androgen-to-estrogen conversion by
aromatase, a CYP enzyme (Gasnier et al., 2009).
Ingested
vitamin A, a fat-soluble vitamin, is delivered to the blood via the
lymph system in chylomicrons, and excess vitamin A is taken up by the
liver as retinoic acid for catabolism by CYP enzymes (Russell, 2000).
Any remaining retinoic acid that is not catabolized is exported inside
LDL particles, and it lingers much longer as retinyl esters in the
vasculature in this form (Krasinski et al., 1990).
Excess retinoic acid is more readily stored in this way in LDL
particles in the elderly. Vitamin A toxicity can lead to fatty liver and
liver fibrosis (Russell, 2000) as well as hypertriglyceridemia (Ellis et al., 1986). Vitamin A has a negative effect on cholesterol sulfate synthesis (Jetten et al., 1989),
which might negatively impact the liver's ability to maintain adequate
supplies of cholesterol sulfate for the bile acids, and therefore also
interfere with the supply of cholesterol sulfate to the gastrointestinal
tract.
In summary, glyphosate's disruption of the CYP
enzymes responsible for RA catabolism could lead to an excess
bioavailability of RA that could contribute adversely to celiac disease,
as well as damaging the liver and leading to teratogenic effects in
offspring of exposed individuals.
In addition to higher risk to birth defects, individuals with celiac disease have increased risk to infertility (Meloni et al., 1999; Farthing et al., 1982).
Increased incidence of hypogonadism, infertility and impotence was
observed in a study of 28 males with celiac disease (Farthing et al., 1982).
Marked abnormalities of sperm morphology and motility were noted, and
endocrine dysfunction was suggested as a probable cause. In studies
conducted on Sertoli cells in prepubertal rat testis, exposure to
Roundup induced oxidative stress leading to cell death (de Liz Oliveira
Cavalli et al., 2013).
Roundup induced the opening of L-type voltage dependent calcium
channels as well as ryanodine receptors, initiating ER stress and
leading to calcium overload and subsequent necrosis. Glutathione was
depleted due to upregulation of several glutathione-metabolizing
enzymes. This suggests that Roundup would interfere with
spermatogenesis, which would impair male fertility.
5 Cobalamin deficiency
Untreated
celiac disease patients often have elevated levels of homocysteine,
associated with folate and/or cobalamin deficiency (Saibeni et al., 2005; Dickey et al., 2008). Species of Lactobacillus and Bifidobacterium have the capability to biosynthesize folate (Rossi et al., 2011),
so their disruption by glyphosate could contribute to folate
deficiency. Malabsorption in the proximal small intestine could also
lead to iron and folate deficiencies. Cobalamin was originally thought
to be relatively spared in celiac disease because its absorption is
mostly through the terminal ileum, which is unaffected by celiac
disease. However, a recent study found that cobalamin deficiency is
prevalent in celiac patients. 41% of the patients studied were found to
be deficient in cobalamin (<220 31="" a="" ahele="" also="" amp="" and="" class=" bibr popnode tag_hotlink tag_tooltip" cobalamin-deficient="" deficiency="" folate="" ghosh="" had="" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945755/?inf_contact_key=e80a2ab822c77742cc6244168c4fb8067fee3cdbc7e3eb6ad6ee4fd4cd224bcf#CIT0051" id="__tag_359830168" ng="" of="" patients="" role="button" these="">2001
).
Either cobalamin or folate deficiency leads directly to impaired
methionine synthesis from homocysteine, because these two vitamins are
both required for the reaction to take place. This induces
hyperhomocysteinemia (Refsum et al., 2001), an established risk factor in association with celiac disease (Hadithi et al., 2009). Long-term cobalamin deficiency also leads to neurodegenerative diseases (Herrmann & Obeid, 2012).
Because
a deficiency in cobalamin can generate a large pool of
methyl-tetrahydrofolate that is unable to undergo reactions, cobalamin
deficiency will often mimic folate deficiency. Cobalamin requires
cobalt, centered within its corrin ring, to function. We depend upon our
gut bacteria to produce cobalamin, and impaired cobalt supply would
obviously lead to reduced synthesis of this critical molecule.
Glyphosate is known to chelate +2 cations such as cobalt. Glyphosate
complexes with cobalt as a dimer [Co(glyphosate)2]3 in fifteen different
stereoisomeric configurations, and it is facile at switching among the
different stereoisomers, an unusual kinetic property compared to most
Co(III) systems (Cusiel, 2005).
In
fact, studies have revealed that glyphosate inhibits other cytosolic
enzymes besides EPSP synthase in plants and microbes that also activate
steps in the shikimate pathway (Ganson and Jensen, 1988; Bode et al., 1984). Glyphosate potently inhibits three enzymes in the shikimate pathway in yeast (Bode et al., 1984).
It has been confirmed that these other enzymes depend upon cobalt as a
catalyst, and glyphosate inhibition works through competitive cobalt
binding and interference with cobalt supply (Ganson and Jensen, 1988).
It has also been proposed that chelation by glyphosate of both cobalt
and magnesium contributes to impaired synthesis of aromatic amino acids
in Escherichia coli bacteria (Hoagland and Duke, 1982). Thus, it is plausible that glyphosate similarly impairs cobalamin function in humans by chelating cobalt.
6 Anemia and iron
Anemia is one of the most common manifestations of celiac disease outside of the intestinal malabsorption issues (Halfdanarson et al., 2007; Bottaro et al., 1999),
and is present in up to half of diagnosed celiac patients. Celiac
patients often have both cobalamin and folate deficiency, which can
cause anemia, but iron deficiency may be the most important factor
(Hershko & Patz, 2008). Celiac patients often don't respond well to iron treatment.
Glyphosate's chelating action can have profound effects on iron in plants (Eker et al., 2006; Bellaloui et al., 2009). Glyphosate interferes with iron assimilation in both glyphosate-resistant and glyphosate-sensitive soybean crops (Bellaloui et al., 2009).
It is therefore conceivable that glyphosate's chelation of iron is
responsible for the refractory iron deficiency present in celiac
disease.
Erythropoietin (EPO), also
called hematopoietin, is a cytokine produced by interstitial fibroblasts
in the kidney that regulates red blood cell production. Low EPO levels,
leading to a low turnover rate of red blood cells, is a feature of
celiac disease (Bergamaschi et al., 2008; Hershko & Patz, 2008).
This can lead to megaloblastic anemia, where red blood cells are large
(macrocytic) and reduced in number due to impaired DNA synthesis. A
recent hematological study on mice exposed to Roundup at subacute levels
for just 15 days revealed an anemic syndrome in both male and female
mice, with a significant reduction in the number of erythrocytes and in
hemoglobin, reduced hematocrit and increased mean corpuscular volume,
indicative of macrocytic anemia (Jasper et al., 2012).
7 Molybdenum deficiency
Molybdenum
deficiency is rarely considered in diagnoses, as it is only needed in
trace amounts. However, molybdenum is essential for at least two very
important enzymes: sulfite oxidase and xanthine oxidase. Sulfite oxidase
converts sulfite, a highly reactive anion, to sulfate, which is much
more stable. Sulfite is often present in foods such as wine and dried
fruits as a preservative. Sulfate plays an essential role in the
sulfated proteoglycans that populate the extracellular matrices of
nearly all cell types (Turnbull et al., 2001; Murch et al., 1993; Murch, 1995).
So, impaired sulfite oxidase activity leads to both oxidative damage
and impaired sulfate supplies to the tissues, such as the enterocytes in
the small intestine. The excess presence of sulfur-reducing bacteria
such as Desulfovibrio in the gut in association with celiac disease
(Collado et al., 2007; Nadal et al., 2007)
could be protective, because these bacteria can reduce dietary sulfite
to hydrogen sulfide, a highly diffusable gas that can migrate through
tissues to provide a source of sulfur for sulfate regeneration at a
distant site, as previously discussed. These distal sites could
reoxidize the H2S through an alternative pathway that does not require molybdenum for sulfur oxidation (Ingenbleek and Kimura, 2013).
Xanthine
oxidase (XO) produces uric acid from xanthine and hypoxanthine, which
are derived from purines. It is activated by iron, which, as we have
seen, is often intractably deficient in association with celiac disease.
Impaired XO activity would be expected to drive purines towards other
degradation pathways. Adenosine deaminase (ADA), a cytoplasmic enzyme
that is involved in the catabolism of purine bases, is elevated in
celiac disease, and is therefore a useful diagnostic marker (Cakal et al., 2010).
In fact, elevation of ADA is correlated with an increase in several
inflammatory conditions. Impaired purine synthesis is expected in the
context of cobalamin deficiency as well, because methyl melonlyl CoA
mutase depends on catalytic action by cobalamin (Allen et al., 1993). Decreased purine synthesis results in impaired DNA synthesis, which then leads to megaloblastic anemia (Boss, 1985),
due to slowed renewal of RBC's from multipotent progenitors, a problem
that is compounded by suppressed EPO activity (Bergamaschi et al., 2008), a feature of celiac disease.
A
remarkable recent case of a three-month old infant suffering from
molybdenum deficiency links several aspects of glyphosate toxicity
together, although glyphosate exposure was not considered as a possible
cause in this case (Boles et al., 1993).
This child presented with microcephaly, developmental delay, severe
irritability, and lactic acidosis. Lactic acidosis is a striking feature
of intentional glyphosate poisoning induced by drinking Roundup
(Zouaoui et al., 2013; Beswick & Millo, 2011), and it suggests impaired oxidative respiration, as is seen in E. coli exposed to glyphosate (Lu et al., 2013).
In vitro studies of glyphosate in the formulation Roundup have
demonstrated an ability to disrupt oxidative respiration by inducing
mitochondrial swelling and inhibiting mitochondrial complexes II and III
(Peixoto, 2005).
This would explain a massive build-up of lactic acid following
ingestion of Roundup, due to a switch to anaerobic metabolism.
Glyphosate has also been shown to uncouple mitochondrial phosphorylation
in plants (Haderly et al., 1977; Ali & Fletcher, 1977).
As
has been stated previously, microcephaly is a feature of excess RA,
which could be induced by glyphosate due to its inhibitory action on CYP
enzymes. In the case study on molybdenum deficiency (Boles et al., 1993),
urinary sulfite levels were high, indicative of defective sulfite
oxidase activity. Serum hypouricemia was also present, indicative of
impaired XO activity. So, the induction of excess RA, depletion of
molybdenum, and lactic acidosis by glyphosate provide a plausible
environmental factor in this case.
One
final aspect of molybdenum deficiency involves nitrate metabolism. As a
source of nitric oxide, inorganic nitrite regulates tissue responses to
ischemia. While nitrate reductase activity has been known to be a
capability of microbes for many years, it has only recently been
realized that mammals also possess a functioning nitrate reductase
capability, utilizing a molybdenum-dependent enzyme to produce nitrite
from nitrate (Jansson et al., 2008).
Molybdenum deficiency would impair this capability, likely contributing
to the higher risk to venous thrombosis observed in celiac disease
(Zenjari et al., 1995; Marteau et al., 1994, Grigg, 1999). This could also explain the excess nitrates in the urine observed in association with celiac disease (Högberg et al., 2011).
8 Selenium and thyroid disorders
Autoimmune thyroid disease is associated with celiac disease (Collin et al., 2002; Valentino et al., 2002). In (Valentino et al., 2002),
up to 43% of patients with Hashimoto's thyroiditis showed signs of
mucosal T-cell activation typical of celiac disease. Selenium, whose
deficiency is associated with celiac disease (Hinks et al., 1984),
plays a significant role in thyroid hormone synthesis, secretion and
metabolism, and selenium deficiency is therefore a significant factor in
thyroid diseases (Sher, 2000; Chanoine et al., 2001; Khrle, 2013).
Selenium
is required for the biosynthesis of the “twenty first amino acid,”
selenocysteine. Twenty five specific selenoproteins are derived from
this amino acid. Selenium deficiency can lead to an impairment in immune
function and spermatogenesis in addition to thyroid function (Papp et al.,
2007).
One very important selenoprotein is glutathione peroxidase, which
protects cell membranes and cellular components against oxidative damage
by both hydrogen peroxide and peroxynitrite (ONOO–) (Prabhakar et al., 2006).
Wheat
can be a good source of selenoproteins. However, the content of
selenium in wheat can range from sufficient to very low, depending upon
soil physical conditions. Soil compaction, which results from modern
practices of “no till” agriculture (Huggins & Reganold, 2008), can lead to both reduced selenium content and a significant increase in arsenic content in the wheat (Zhao et al., 2007). Since glyphosate has been shown to deplete sulfur in plants (Saes Zobiole et al., 2010),
and selenium is in the same column of the periodic table as sulfur, it
is likely that glyphosate also disrupts selenium uptake in plants. A
gluten-free diet will guarantee, however, that no selenium is available
from wheat, inducing further depletion of selenoproteins, and therefore
increasing the risk to immune system, thyroid and infertility problems
in treated celiac patients.
The gut bacterium Lactobacillus, which is negatively impacted by glyphosate (Shehata et al., 2013) and depleted in association with celiac disease (Di Cagno et al., 2011), is able to fix inorganic selenium into more bioavailable organic forms like selenocysteine and selenomethionine (Pessione, 2012). Selenocysteine is present in the catalytic center of enzymes that protect the thyroid from free radical damage (Triggiani et al., 2009).
Free radical damage would lead to apoptosis and an autoimmune response
(Tsatsoulis, 2002). Glyphosate's disruption of these bacteria would lead
to a depletion in the supply of selenomethionine and selenocysteine.
Methionine depletion by glyphosate (Nafziger et al., 1984) would further compound this problem.
Thus,
there are a variety of ways in which glyphosate would be expected to
interfere with the supply of selenoproteins to the body, including its
effects on Lactobacillus, its depletion of methionine, the no-till
farming methods that are possible because weeds are killed chemically,
and the likely interference with plant uptake of inorganic selenium.
This aligns well with the observed higher risk of thyroid problems in
association with celiac disease, in addition to infertility problems and
immune issues, which are discussed elsewhere in this paper. Further
support for an association between glyphosate and thyroid disease comes
from plots over time of the usage of glyphosate in the U.S. on corn and
soy time-aligned with plots of the incidence rate of thyroid cancer in
the U.S., as shown in Figure 3.
Thyroid cancer incidence rate plotted against glyphosate applied to U.S. corn & soy crops (R=0.988, p≤7.612e-09) along with % GE corn & soy crops (R=0.9377, p≤2.152e-05). Sources: USDA:NASS; SEER. (Figure courtesy of Nancy ...
9 Indole and kidney disease
The
prevalence of kidney disease and resulting dialysis is increasing
worldwide, and kidney disease is often associated with increased levels
of celiac disease autoantibodies. Kidney disease and thyroid dysfunction
are intimately connected (Iglesias & DÃez, 2009).
A population-based study in Sweden involving nearly 30,000 people with
diagnosed celiac disease determined that there was nearly a three-fold
increased risk for kidney failure in this population group (Welander et al., 2012).
Inflammation plays a crucial role in kidney disease progression (Tonelli et al., 2005; Bash et al., 2009; Rodriguez-Iturbe et al., 2010).
Chronic kidney disease develops as a consequence of assaults on the
kidney from inflammatory agents, brought on by the induction of
pro-inflammatory cytokines and chemokines in the kidney. The toxic
phenol p-Cresol sulfate, as well as indoxyl sulfate, a molecule that is
chemically similar to p-Cresol, have been shown to induce activation of
many of these cytokines and chemokines (Sun et al., 2012). p-Cresol and indoxyl sulfate both decrease endothelial proliferation and interfere with wound repair (Dou et al., 2004).
p-Cresol is produced by the pathogenic bacterium C. difficile, and
indoxyl sulfate, derived from indole through sulfation in the liver
(Banoglu & King, 2002), accumulates at high levels in association with chronic kidney disease (Niwa, 2010).
The
aromatic amino acid tryptophan contains an indole ring, and therefore
disruption of tryptophan synthesis might be expected to generate indole
as a by-product. Indeed, glyphosate has been shown to induce a
significant increase in the production of indole-3-acetic acid in yellow
nutsedge plants (Caal et al., 1987). Indole is produced by
coliform microorganisms such as E. coli under anaerobic conditions.
Glyphosate induces a switch in E. coli from aerobic to anaerobic
metabolism due to impaired mitochondrial ATP synthesis (Lu et al., 2013; Samsel & Seneff, 2013),
which would likely result in excess production of indole. Besides, E.
coli, many other pathogenic bacteria can produce indole, including
Bacillus, Shigella, Enterococcus, and V. cholerae (Lee & Lee, 2010).
At least 85 different species of both Gram-positive and Gram-negative
bacteria produce indole, and its breakdown by certain bacterial species
depends on CYP enyzmes (Lee & Lee, 2010). Feeding indole to rats deprived of sulfur metabolites leads to macrocytic anemia (Roe, 1971). Indole is an important biological signaling molecule among microbes (Lee & Lee, 2010).
Indole acetic acid inhibits the growth of cobalamin-dependent
microorganisms, which then causes macrocytic (pernicious) anemia in the
host due to cobalamin deficiency (Drexler, 1958).
Experiments
on exposure of mouse fetuses to indole-3-acetic acid have shown that it
dramatically induces microcephaly in developing fetuses exposed at
critical times in development (Furukawa et al., 2007). A case study found celiac disease associated with microcephaly and developmental delay in a 15-month-old girl (Bostwick et al., 2001; Lapunzina, 2002).
A gluten-free diet restored head growth. The authors suggested that
poor head growth might precede other manifestations of celiac disease in
infants. A study on plants demonstrated a concentration gradient of
indole-3-acetic acid in the plant embryo, similar to the gradient in
retinoic acid that controls fetal development in mammals (Uggla et al., 1996). This alternative may be another way in which glyphosate would promote microcephaly.
Thus,
solely through its effect on indole production and indole catabolism in
gut bacteria, chronic glyphosate exposure would be expected to lead to
cobalamin deficiency, pernicious anemia, microcephaly in a fetus during
pregnancy, and kidney failure. p-Cresol supply by overgrown pathogens
like C. difficile would likely contribute in a similar way as indole,
due to its similar biochemical and biophysical properties.
10 Nutritional deficiencies
The
damaged villi associated with celiac disease are impaired in their
ability to absorb a number of important nutrients, including vitamins
B6, B12 (cobalamin) and folate, as well as iron, calcium and vitamins D
and K (Hallert et al., 2002).
Thus, long-term celiac disease leads to major deficiencies in these
micronutrients. Cobalamin deficiency has been well addressed previously.
We have also already mentioned the chelation of trace minerals by
phytates and by glyphosate. However, other factors may be at play as
well, as discussed here.
Glyphosate disrupts the
synthesis of tryptophan and tyrosine in plants and in gut bacteria, due
to its interference with the shikimate pathway (Lu et al., 2013; MarÃa et al.,
1996), which is its main source of toxicity to plants. Glyphosate also
depletes methionine in plants and microbes. A study on serum tryptophan
levels in children with celiac disease revealed that untreated children
had significantly lower ratios of tryptophan to large neutral amino
acids in the blood, and treated children also had lower levels, but the
imbalance was less severe (Hernanz & Polanco, 1991).
The authors suggested a metabolic disturbance in tryptophan synthesis
rather than impaired absorption, as other similar amino acids were not
deficient in the serum. It was proposed that this could lead to
decreased synthesis of the monoamine neurotransmitter, serotonin, in the
brain associated with behavior disorders in children with celiac
disease, such as depression (Koyama & Melzter, 1986). Deficiencies in tyrosine and methionine were also noted (Hernanz & Polanco, 1991).
“Functional dyspepsia” is an increasing and mainly intractable problem
in the Western world, which is estimated to affect 15% of the U.S.
population (Saad & Chey, 2006).
Dyspepsia, a clinical symptom of celiac disease, is likely mediated by
excess serotonin synthesis following ingested tryptophan-containing
foods (Manocha et al., 2012).
Serotonin
(5-hydroxytryptamine or 5-HT) is produced by enterochromaffin (EC)
cells in the gut and is an important signaling molecule for the enteric
mucosa (Kim et al., 2001).
EC cells are the most numerous neuroendocrine cell type in the
intestinal lumen, and they regulate gut secretion, motility, pain and
nausea by activating primary afferent pathways in the nervous system
(Chin et al., 2012).
Serotonin plays an important role in activating the immune response and
inflammation in the gut, and also induces nausea and diarrhea when it
is overexpressed. Anaerobic bacteria in the colon convert sugars into
short-chain fatty acids, which can stimulate 5-HT release from EC cells
(Fukumoto et al., 2003; Grider & Piland, 2007).
This is likely an important source of fats to the body in the case of a
low-fat diet induced by impaired fatty acid metabolism due to
insufficient bile acids.
The number of 5-HT expressing
EC cells in the small intestine is increased in association with celiac
disease, along with crypt hyperplasia (Wheeler & Challacombe, 1984; Challacombe et al., 1977),
and, as a consequence, serotonin uptake from dietary sources of
tryptophan is greatly increased in celiac patients (Erspamer, 1986).
Postprandial dyspepsia is associated in celiac disease with increased
release of 5-HT, and this may account for the digestive symptoms
experienced by celiac patients (Coleman et al., 2006).
An explanation for these observations is that a chronic tryptophan
insufficiency due to the impaired ability of gut bacteria to produce
tryptophan induces aggressive uptake whenever dietary tryptophan is
available.
Glyphosate forms strong complexes with
transition metals, through its carboxylic, phosphonic, and amino
moieties, each of which can coordinate to metal ions, and it can also
therefore form complexes involving two or three atoms of the targeted
transition metal (Madsen et al., 1978; Motekaitis & Martell, 1985; Undabeytia et al., 2002).
This means that it is a metal chelator par excellence. One can expect,
therefore, deficiencies in multiple transition (trace) metals, such as
iron, copper, cobalt, molybdenum, zinc and magnesium in the presence of
glyphosate. Glyphosate has been shown to reduce levels of iron,
magnesium, manganese and calcium in non-GMO soybean plants (Cakmak et al., 2009). We have already discussed iron, selenium, cobalt and molybdenum deficiencies in association with celiac disease.
Zinc
deficiency seems to be a factor in celiac disease, as a recent study of
30 children with celiac disease demonstrated a significantly reduced
serum level of zinc (0.64 vs 0.94 µg/mL in controls) (Singhal et al., 2008). Copper deficiency is a feature of celiac disease (Halfdanarson et al., 2009),
and copper is one of the transition metals that glyphosate binds to and
chelates (Madsen, 1978; Undabeytia, 2002). Confirmed magnesium
deficiency in celiac disease has been shown to be due to significant
loss through the feces (Goldman et al., 1962).
This would be expected through binding to phytates and/or glyphosate. A
study of 23 patients with gluten-sensitive enteropathy to assess
magnesium status revealed that only one had serum magnesium levels below the normal range, whereas magnesium levels in erythrocytes and lymphocytes was markedly below normal, and this was associated with evidence of osteoporosis due to malabsorption (Rude and Olerich, 1996). Daily treatment with MgCl2 or Mg lactate led to a significant increase in bone mineral density, and was correlated with a rise in RBC Mg2+.
A recent study investigated the status of 25(OH) vitamin D3 in adults and children with celiac disease (Lerner et al., 2012).
It was determined that vitamin D3 deficiency was much more prevalent in
the adults than in the children, suggesting a deterioration in vitamin
D3 serum levels with age. This could be explained by a chronic
accumulation of glyphosate, leading to increasingly impaired vitamin D3
activation in the liver. The liver converts 1,25(OH) vitamin D3 to the
active form, 25(OH) vitamin D3, using CYP27A (Ponchon et al., 1969; Sakaki et al., 2005), which might be disrupted by glyphosate exposure, given its known interference with CYP function in mice (Hietanen et al., 1983). On a broader level, this might also explain the recent epidemic in the U.S. in vitamin D3 deficiency (Holick, 2005).
Another
issue to consider is whether the food being consumed by celiac patients
is itself depleted in nutrients. This is likely the case for the
transgenic Roundup-Ready crops that increasingly supply the processed
food industry. A recent study on the effects of glyphosate on
Roundup-Ready soy revealed a significant effect on growth, as well as an
interference with the uptake of both macronutrients and micronutrients
(Saes Zobiole et al., 2010).
Transgenic soybeans exposed to glyphosate are often affected by a
“yellow flashing” or yellowing of the upper leaves, and an increased
sensitivity to water stress. An inverse linear relationship was observed
between glyphosate dosage and levels of the macronutrients, sodium,
calcium, sulfur, phosphorus, potassium, magnesium, and nitrogen, as well
as the micronutrients, iron, zinc, manganese, copper, cobalt,
molybdenum, and boron. Glyphosate's ability to form insoluble metal
complexes likely mediates these depletions (Glass, 1984). Glyphosate also interferes with photosynthesis, as reflected in several measures of photosynthesis rate (Saes et al., 2010) and reductions in chlorophyll (Ali & Fletcher, 1977; Kitchen et al., 1981).
This could be due to depletion of zinc and manganese, since
chloroplasts require these micronutrients to function well (Homann, 1967; Thompson & Weier, 1962).
11 Cancer
Chronic
inflammation, such as occurs in celiac disease, is a major source of
oxidative stress, and is estimated to account for 1/3 of all cancer
cases worldwide (Ames et al., 1993; Coussens & Werb, 2002).
Oxidative stress leads to DNA damage and increased risk to genetic
mutation. Several population-based studies have confirmed that patients
with celiac disease suffer from increased mortality, mainly due to
malignancy (Nielsen et al., 1985; Logan et al., 1989; Pricolo et al., 1998; Cottone et al., 1999; Corrao et al., 2001; Green et al., 2003).
These include increased risk to non-Hodgkin's lymphoma, adenocarcinoma
of the small intestine, and squamous cell carcinomas of the esophagus,
mouth, and pharynx, as well as melanoma. The non-Hodgkin's lymphoma was
not restricted to gastrointestinal sites, and the increased risk
remained following a gluten-free diet (Green et al., 2003).
Celiac
disease is associated with a lifelong risk of any malignancy between
8.1 and 13.3%, with the risk for non-Hodgkin's lymphoma alone being 4.3
to 9.6% (Matheus-Vliezen et al., 1994; Egan et al., 1995).
This risk is 19-fold higher than the risk in the general population.
Selenium deficiency in association with celiac disease may be a
significant factor in the increased cancer risk. Selenium deficiency is
associated with increased risk to several cancers, and selenium
supplements are beneficial in reducing the incidence of liver cancer and
decreasing mortality in colorectal, lung and prostate cancer (Nelson et al., 1999; Björnstedt et al., 2010).
Children
with celiac disease, whether or not they are on a gluten-free diet,
exhibit elevated urinary biomarkers of DNA damage (Zaflarska-Popawska et al., 2010).
Human colon carcinoma cells exposed to peptides extracted from wheat
responded with a sharp increase in the GSSG/GSH ratio (ratio of oxidized
to reduced glutathione), a well-established indicator of oxidative
stress (Rivabene, 1999).
The authors did not provide information as to whether the wheat plants
were exposed to glyphosate, but they did suggest that this effect could
explain the increased risk to intestinal cancer associated with celiac.
Intriguingly, studies on pea plants have shown that glyphosate induces a sharp increase in the GSSG/GSH ratio in plants (Miteva et al., 2003), which suggests that glyphosate contamination could explain the results observed in (Rivabene, 1999).
Interestingly,
it was noted in 1996 that the incidence of both non-Hodgkin's lymphoma
and melanoma had been rising sharply worldwide in recent decades, and so
it was decided to investigate whether there might be a link between the
two cancers associated with sunlight exposure. Surprisingly, the
authors found an inverse relationship between non-Hodgkin's
lymphoma and UV exposure. More recently, such UV protection has been
reaffirmed in a review of epidemiologic studies on the subject (Negri, 2010).
This suggests that vitamin D3 is protective, so vitamin D3 deficiency
due to impaired CYP function in the liver could be contributory to
increased risk in celiac disease.
The incidence of
non-Hodgkins lymphoma has increased rapidly in most Western countries
over the last few decades. Statistics from the American Cancer Society
show an 80% increase since the early 1970's, when glyphosate was first
introduced on the market.
While there
have been only a few studies of lymphoma and glyphosate, nearly all have
indicated a potential relationship (Vigfusson & Vyse, 1980; Pavkov & Turnier, 1986; Hardell & Eriksson, 1999; McDuffie et al., 2001; De Roos et al., 2003).
A dose-response relationship for non-Hodgkin's lymphoma was
demonstrated in a cross-Canada study of occupational exposure to
glyphosate in men (McDuffie et al., 2001), and a larger study in the U.S. noted a similar result (De Roos et al., 2003).
A population-based study in Sweden showed an increased risk to
non-Hodgkins lymphoma upon prior exposure to herbicides and fungicides
but not insecticides (Hardell & Eriksson, 1999).
Glyphosate exposure resulted in an odds ratio of 2.3, although the
number of samples was small, and the authors suggested that further
study is necessary. A study on mice showed increases in carcinoma,
leukemia and lymphoma (Pavkov & Turnier, 1986) and an in vitro mutagenic test on human lymphocytes revealed increased sister-chromatid exchanges (Vigfusson & Vyse, 1980) upon exposure to glyphosate.
12 Proposed transglutaminase-glyphosate interactions
Establishing
the mechanism by which glyphosate might promote autoantibodies to
transglutaminase is a challenging task, not because this possibility
seems unlikely but rather because multiple disruptions are plausible. In
this section, we present evidence from the research literature that
supports various hypotheses for the interaction of glyphosate with the
transglutaminase enzymatic pathways. The definitive studies that clarify
which of these hypotheses is correct have yet to be conducted.
Celiac
disease is thought to be primarily caused by ingestion of wheat gluten
proteins, particularly gliadin, due to a high concentration of proline-
and glutamine-rich sequences, which imparts resistance to degradation by
proteases. Transglutaminase autoimmunity arises when specific epitopes
of wheat gliadin activate sensitized T-cells which then stimulate B-cell
synthesis of IgA or IgM autoantibodies to transglutaminase.
Transglutaminase bound to gliadin can induce false recognition by a
T-cell.
Transglutaminase acts on gluten in wheat to
form crosslinks between glutamine residues and lysine residues,
producing ammonia as a by-product. Ammonia is known to induce greater
sensitivity to glyphosate in plants, and it is common practice to apply
ammonium sulfate simultaneously with glyphosate for this reason
(Nalewaja & Matysiak, 1993).
This enhanced effect is due to ammonium binding to glyphosate at three
sites – one on the carbonyl group and two on the phosphonyl group, which
displaces cations such as calcium and endows glyphosate with enhanced
reactivity.
Transglutaminase sometimes only achieves
half of its intended reaction product, by converting a glutamine residue
to glutamate, and leaving lysine intact, thus not producing the desired
crosslink. It has been established that gluten fragments containing
“deamidated glutamine” residues instead of the crosslinks are much more
highly allergenic than those that contain the crosslinks (Dørum et al., 2010; Qiao et al., 2005).
These have been referred to as “celiac disease T-Cell epitopes.”
T-cells of celiac patients preferentially recognize epitopes that are
augmented with negatively charged deamidated glutamine residues – the
product of the reaction when the lysine linkage does not occur. Thus, if
there is a mechanism by which glyphosate interferes with crosslink
formation, this would explain its ability to enhance gluten sensitivity.
A
clue can be found from the research literature on glyphosate
sensitivity in plants, where it has been determined that the
substitution of a lysine residue in a critical locale in EPSP synthase
greatly increases sensitivity to glyphosate (Selvapandiyan et al., 1995).
Lysine's NH3+ group is highly reactive with negatively charged ions,
and this makes it a common constituent of DNA binding proteins due to
its ability to bind to phosphates in the DNA backbone. Glyphosate
contains a phosphonyl group that binds easily to ammonia and behaves as a
phosphate mimetic. It also contains a carboxyl group that substitutes
well for the carboxyl group of glutamate, the intended reaction partner.
Thus,
it seems possible that glyphosate would be drawn to the ammonia
released when the glutamine residue is deamidated by transglutaminase,
and then the ammonium glyphosate would react with the lysine residue,
releasing the ammonia and resulting in the binding of glyphosate to the
lysine residue. This would yield a gluten fragment bound to glyphosate
that is likely highly allergenic. An analogous EPSP
synthase-EPSP-glyphosate ternary complex has been identified in numerous
studies on the physiology of glyphosate in plants (Sammons et al., 1995).
Research
in the food industry has concerned producing breads that, while not
gluten free, may contain forms of gluten to which celiac patients are
less sensitive. Such research has revealed that enzymatic modification
to promote methionine binding to glutamine reduces IgA immunoreactivity
(Cabrera-Chávez et al., 2010).
Whether methionine binding to glutamine residues in wheat takes place
in vivo is not known, but it is established that glyphosate depletes
methionine by 50 to 65 percent in plants, as well as the aromatic amino
acids (Nafziger et al., 1984; Haderlie et al., 1977).
As we have already discussed, glyphosate interferes with cobalt
bioavailability for cobalamin synthesis, and cobalamin is an essential
catalyst for the conversion of cysteine to methionine.
Transglutaminase
also cross-links proteins in the extracellular matrix, and therefore is
important for wound healing, tissue remodeling, and stabilization of
the extracellular matrix. Thus, autoimmunity to transglutaminase leads
to destabilization of the microvilli lining the small intestines.
Transglutaminase has 18 free cysteine residues which are targets for
S-nitrosylation. A cysteine residue is also involved in the catalytic
active site. A unique Ca2+ dependent mechanism regulates
nitrosylation by NO, mediated by CysNO (S-nitrosocysteine). It was shown
experimentally that up to 15 cysteines of transglutaminase were
nitrosylated by CysNO in the presence of Ca2+, and this inhibited its enzymatic activity (Lai et al., 2001).
Thus,
another plausible mechanism by which glyphosate might enhance the
development of autoantibodies to transglutaminase is by nitrosylating
its cysteines, acting similarly to CysNO. A precedent for this idea is
set with research proposing nitrosylation as the means by which
glyphosate interferes with the heme active site in CYP enzymes (Lamb et al., 1998).
It is conceivable that cysteine nitrosylation by glyphosate at the
active site inactivates the molecule, in which case glyphosate is itself
acting as an “antibody.”
13 Evidence of glyphosate exposure in humans and animals
The
US EPA has accepted Monsanto's claim that glyphosate is essentially
harmless to humans. Due to this position, there have been virtually no
studies undertaken in the US to assess glyphosate levels in human blood
or urine. However, a recent study involving multiple countries in Europe
provides disturbing confirmation that glyphosate residues are prevalent
in the Western diet (Hoppe, 2013).
This study involved exclusively city dwellers, who are unlikely to be
exposed to glyphosate except through food sources. Despite Europe's more
aggressive campaign against GMO foods than that in the Americas, 44% of
the urine samples contained quantifiable amounts of glyphosate. Diet
seems to be the main source of exposure. One can predict that, if a
study were undertaken in the U.S., the percentage of the affected
population would be much larger.
A recent study
conducted on dairy cows in Denmark shows conclusively that the cows’
health is being adversely affected by glyphosate (Krüger et al., 2013a).
All of the cows had detectable levels of glyphosate in their urine, and
it was estimated that from 0.1 to 0.3 mg of glyphosate was excreted
daily from each cow. More importantly, all of the cows had serum levels
of cobalt and manganese that were far below the minimum reference level
for nutrient sufficiency. Half of the cows had high serum urea, and
there was a positive linear relationship between serum urea and
glyphosate excretion. High serum urea is indicative of nephrotoxicity.
Blood serum levels of enzymes indicative of cytotoxicity such as
creatine kinase (CK) and alkaline phosphatase (ALP) were also elevated.
CK is indicative of rhabdomyolysis or kidney failure. High levels of ALP
indicate liver damage, and it is often used to detect blocked bile
ducts (Kaplan et al., 1983).
Thus,
the low cobalt levels and the indicators of liver, kidney, and gall
bladder stress are all consistent with our previous discussion. The
results of this study were also consistent with results of a study on
rats exposed experimentally to glyphosate (Beuret et al., 2005) in which Roundup was shown to be even more toxic than its active ingredient, glyphosate.
Glyphosate-metal
complexes serve to reduce glyphosate's toxicity in the soil to plants,
but they also protect glyphosate from attack by microorganisms that
could decompose it (Cusiel, 2005).
The degree of reactivity of the complex depends on which metals
glyphosate binds to, which in turn depends upon the particular soil
conditions (Nomura & Hilton, 1977). Glyphosate usually degrades relatively quickly (Vencill, 2002);
however, a half-life of up to 22 years has also been reported in
conditions where pH is low and organic matter contents are high (Nomura
& Hilton, 1977).
Therefore, glyphosate may survive much longer in certain soils than has
been claimed by the industry, and could be taken up by crops planted
subsequent to glyphosate application to kill weeds.
A disturbing trend of crop desiccation by glyphosate pre-harvest (O'Keeffe, 1980; O'Keeffe, 1981; Stride et al., 1985; Darwent et al., 1994; Orson & Davies, 2007)
may be a key factor in the increased incidence of celiac disease.
According to Monsanto, glyphosate was used on some 13% of the wheat area
pre-harvest in the UK in 2004. However, by 2006 and 2007, some 94% of
UK growers used glyphosate on at least 40% of cereal and 80% of oilseed
crops for weed control or harvest management (Monsanto International
SÃ rl, 2010).
An
increasing number of farmers now consider the benefits of desiccating
their wheat and sugar cane crops with glyphosate shortly before the
harvest (Monsanto International SÃ rl, 2010).
The advantage is improved harvesting efficiency because the quantity of
materials other than grain or cane is reduced by 17%, due to a shutdown
of growth following glyphosate treatment. Treated sugar cane crops
produce drier stalks which can be baled more easily. There is a shorter
delay before the next season's crop can be planted, because the
herbicide was applied pre-harvest rather than post-harvest. Several
pests can be controlled due to the fact that glyphosate is a
broad-spectrum herbicide. These include Black grass, Brome grasses, and
Rye grasses, and the suggestion is that this would minimize the risk of
these weeds developing resistance to other herbicides.
A complete list of the latest EPA residue levels for glyphosate as of September 18, 2013 are shown in Table 1. Tolerances are established on all crops for both human and animal consumption resulting from the application of glyphosate.
Complete
list of glyphosate tolerances for residues in food crops in the U.S. as
of September 18, 2013, as reported in: EPA: Title 40: Protection of
Environment.
As glyphosate usage continues unabated, glyphosate resistance among weeds is becoming a growing problem (Waltz, 2010),
necessitating a strategy that either involves an increase in the amount
of glyphosate that is applied or a supplementation with other
herbicides such as glufosinate, dicampa, 2-4D, or atrazine. Agrochemical
companies are now actively developing crops with resistance to multiple
herbicides (Culpepper, 2000),
a disturbing trend, especially since glyphosate's disruption of CYP
enzymes leads to an impaired ability to break down many other
environmental chemicals in the liver.
14 Kidney disease in agricultural workers
Chronic kidney disease is a globally increasing problem (Ramirez-Rubio et al., 2013),
and glyphosate may be playing a role in this epidemic. A plot showing
recent trends in hospitalization for acute kidney injury aligned with
glyphosate usage rates on corn and soy shows strong correlation, as
illustrated in Figure 4, and a similar correlation is seen for deaths due to end-stage renal disease in Figure 5.
Recently, it has been noted that young men in Central America are
succumbing in increasing numbers to chronic kidney disease (Trabanino et al., 2002; Cerdas, 2005; Torres et al., 2010; Peraza et al., 2012; Ramirez-Rubio et al., 2013; Sanoff et al., 2010). The problem appears to be especially acute among agricultural workers, mainly in sugar cane fields (Cerdas, 2005; Torres et al., 2010; Peraza et al., 2012).
Since we have shown in Section 8 how glyphosate can produce toxic
effects on the kidneys through its disruption of gut bacteria, it is
fruitful to consider whether glyphosate could be playing a role in the
fate of Central American workers in the sugar cane fields.
Number
of hospitalizations for acute kidney injury plotted against glyphosate
applied to com & soy (in 1000 tons). (Figure courtesy of Nancy
Swanson).
End
stage renal disease deaths (ICD N18.0 & 585.6) plotted against % GE
corn & soy planted (R=0.9585, p<4 .03e-6="" amp="" and="" applied="" corn="" em="" glyphosate="" soy="" to="">p≤
3.704e-09). Sources: USDA:NASS; CDC. (Figure courtesy ...
In
attempting to explain this phenomenon, physicians and pharmacists have
proposed that it may be due to dehydration caused by over-exertion in
high temperature conditions, combined with an acute reaction to commonly
administered non-steroidal anti-inflammatory drugs (NSAIDs) to treat
pain and/or antibiotics to treat infection (Ramirez-Rubio et al., 2013). NSAIDs require CYP enzymes in the liver for detoxification (Agúndez et al., 2009),
so impaired CYP function by glyphosate would lead to a far more toxic
effect of excessive NSAID administration. Kidney disease among
agricultural workers tends to be associated with chronic
glomerulonephritis and interstial nephritis, which was proposed in
(Soderland et al., 2010)
to be due to environmental toxins such as heavy metals or toxic
chemicals. Glomerulonephritis is also found in association with celiac
disease (Katz et al., 1979; Peters et al., 2003). A Swedish study showed a five-fold increase in nephritis risk in celiac patients (Peters et al., 2003).
A strong hint comes from epidemiological studies conducted in Costa Rica (Cerdas, 2005).
The demographic features of those with chronic renal failure revealed a
remarkably specific pattern of young men, between 20 and 40 years old,
with chronic interstitial nephritis. All of them were sugar-cane
workers. These authors wrote: ”A specific study of their work
environment is needed to determine what in their daily activities puts
them at increased risk for chronic renal failure.”
Agriculture
is an important part of the economy of the state of Louisiana in the
United States, and sugar cane is a significant agricultural product.
Chemical methods to ripen sugar cane are commonly used, because they can
substantially increase the sucrose content of the harvest (Richard
& Dalley, 2009). Glyphosate, in particular, has been the primary ripener used in Louisiana since 1980 (Orgeron, 2012).
As of 2001, Louisiana had the highest rate of kidney failure in the
U.S. (State-Specific Trends in Chronic Kidney Failure – United States, 1990–2001).
Louisiana's death rate per 100,000 from nephritis/kidney disease is
26.34 as compared to a U.S. rate of 14.55 (Network Coordinating Council,
2013). The number of patients on dialysis has risen sharply in the last few years.
By
2005, it is estimated that 62% of the total harvested hectares of sugar
cane in Louisiana were ripened with glyphosate (Legendre et al., 2005). A paper published in 1990 showed that glyphosate applied as a ripener on three different sugar cane varieties grown in Costa Rica produced up to a 15% increase in the sucrose content of the harvested sugar cane (Subiros, 1990). Glyphosate applied before the harvest is the only sugarcane ripener currently registered for use in the U.S.
A
disturbing recent trend is the repeated application of glyphosate over
the course of the season with the hope of further increasing yields
(Richard & Dalley, 2009).
Responses to the standard application rate (0.188 lb/acre) of
glyphosate have been inconsistent, and so farmers are increasing both
the amount and the frequency of application. In (Richard & Dalley, 2009),
growers are encouraged not to apply glyphosate beyond mid-October, as
results are counterproductive, and not to use higher rates in an attempt
to improve yield. But it is doubtful that these recommendations are
being followed. It is likely, although we have not been able to confirm
this, that glyphosate usage has expanded in scope on the sugar cane
fields in Central America since 2000, when the expiration of Monsanto's
patent drove prices down, and that the practices of multiple
applications of glyphosate in the U.S. are also being followed in
Central America. Several other ripening agents exist, such as Ethephon,
Trinexapacethyl, and Sulfometuron-methyl, but glyphosate is likely
growing in popularity recently due to its more favorable pricing and
perceived non-toxicity. Larger amounts are needed for effective ripening
in regions that are hot and rainy, which matches the climate of Costa
Rica and Nicaragua.
15 Discussion
In
this paper, we have developed an argument that the alarming rise in the
incidence of celiac disease in the United States and elsewhere in
recent years is due to an increased burden of herbicides, particularly
glyphosate exposure in the diet. We suggest that a principal factor is
the use of glyphosate to desiccate wheat and other crops prior to the
harvest, resulting in crop residue and increased exposure. Strong
evidence for a link between glyphosate and celiac disease comes from a
study on predatory fish, which showed remarkable effects in the gut that
parallel the features of celiac disease (Shenapati et al., 2009).
More
generally, inflammatory bowel disease has been linked to several
environmental factors, including a higher socioeconomic status, urban as
opposed to rural dwelling, and a “Westernized” cultural context
(Shapira et al., 2010).
Disease incidence is highest in North America and Europe, and is higher
in northern latitudes than in southern latitudes within these regions,
suggesting a beneficial role for sunlight. According to the most recent
statistics from the U.S. Environmental Protection Agency (EPA) (Grube et al., 2011),
the U.S. currently represents 25% of the total world market on
herbicide usage. Glyphosate has been the most popular herbicide in the
U.S. since 2001, whereas it was the 17th most popular herbicide in 1987
(Kiely et al., 2004).
Since 2001, glyphosate usage has grown considerably, due to increased
dosing of glyphosate-resistant weeds and in conjunction with the
widespread adoption of “Roundup-Ready” genetically modified crops.
Glyphosate is probably now the most popular herbicide in Europe as well
(Kimmel et al., 2013).
Glyphosate has become the number one herbicide worldwide, due to its
perceived lack of toxicity and its lower price after having become
generic in 2000 (Duke & Powles, 2008).
A recent estimate suggests that one in twenty people in North America and Western Europe suffer from celiac disease (Koning, 2005; Fasano et al., 2003). Outdoor occupational status is protective (Sonnenberg et al., 1991).
First generation immigrants into Europe or North America are generally
less susceptible, although second generation non-Caucasian immigrants
statistically become even more susceptible than native Caucasians
(Shapira et al., 2010). This may in part stem from the increased need for sunlight exposure given darker skin pigmentation.
Table 2
summarizes our findings relating glyphosate to celiac disease. All of
the known biological effects of glyphosate – cytochrome P450 inhibition,
disruption of synthesis of aromatic amino acids, chelation of
transition metals, and antibacterial action – contribute to the
pathology of celiac disease.
Illustration of the myriad ways in which glyphosate can be linked to celiac disease or its associated pathologies.
(b) Transition metal chelation
(c) CYP enzyme inhibition
(d) Shikimate pathway suppression
Celiac
disease is associated with deficiencies in several essential
micronutrients such as vitamin D3, cobalamin, iron, molybdenum, selenium
and the amino acids, methionine and tryptophan, all of which can be
explained by glyphosate. Glyphosate depletes multiple minerals in both
genetically modified soybeans (Saes et al., 2010) and conventional soybeans (Cakmak et al., 2009),
which would translate into nutritional deficiencies in foods derived
from these crops. This, together with further chelation in the gut by
any direct glyphosate exposure, could explain deficiencies in cobalt,
molybdenum and iron. Glyphosate's effect on CYP enzymes should lead to
inadequate vitamin D3 activation in the liver (Hietanen et al., 1983; Ponchon et al., 1969).
Cobalamin depends on cobalt, and cobalt-dependent enzymes in plants and
microbes have been shown to be inhibited by glyphosate (Bode et al., 1984; Ganson and Jensen, 1988). Glyphosate has been shown to severely impair methionine and tryptophan synthesis in plants (Nafziger et al., 1984), which would reduce the bioavailability of these nutrients in derived foods.
There
are multiple intriguing connections between celiac disease and
microcephaly, all of which can be linked to glyphosate. Celiac disease
is found in association with microcephaly in infants (Bostwick et al., 2001; Lapunzina, 2002), and teratogenic effects are also observed in children born to celiac mothers (Dickey et al., 1996; Martinelli et al., 2000). Microcephaly in an infant where confirmed molybdenum deficiency was present (Boles et al., 1993)
suggests that molybdenum deficiency could be causal. However, elevated
RA also induces microcephaly, as does indole-3-acetic acid, which has
been dramatically linked to microcephaly in mice (Furukawa et al., 2007).
Elevated RA is predicted as a response to glyphosate due to its
expected inhibition of CYP enzymes which catabolize RA in the liver
(Lamb et al., 1998; Hietanen et al., 1983).
Molybdenum deficiency is expected due to glyphosate's ability to
chelate cationic minerals. Glyphosate has been shown to induce
indole-3-acetic acid synthesis in plants (Caal et al., 1987), and it induces a shift to anaerobic metabolism in E. coli (Lu et al., 2013), which is associated with indole synthesis.
Celiac
disease is associated with impaired serotonin metabolism and signaling
in the gut, and this feature leads us to propose a novel role for
serotonin in transporting sulfate to the tissues. It is a curious and
little known fact that glucose and galactose, but not fructose or
mannose, stimulate 5-HT synthesis by EC cells in the intestinal lumen
(Kim et al., 2001),
suggesting a role for EC cells as “glucose sensors.” Glucose and
galactose are the two sugars that make up the heparan sulfate chains of
the syndecans and glypicans that attach to the membrane-bound proteins
in most cells, serving as the innermost constituency of the
extracellular matrix (Bernfield et al., 1999). In (Seneff et al., 2012),
it was proposed that part of the post-prandial glucose that is taken up
by the tissues is temporarily stored in the extracellular matrix as
heparan sulfate, and that a deficiency in sulfate supply impairs this
process, which impedes glucose uptake in cells. These heparan sulfate
units have a high turnover rate, as they are typically broken down
within three hours of their initial placement (Turnbull et al., 2001).
This provides the cells with a convenient temporary buffer for glucose
and galactose that can allow them to more efficiently remove these
sugars from the serum. Insufficient sulfate supplies would impair this
process and lead to insulin resistance.
As is the case
for other monoamine neurotransmitters as well as most sterols, 5-HT is
normally transported in the serum in a sulfated form. The sulfate moiety
must be removed for the molecule to activate it. Therefore, 5-HT, as
well as these other monoamine neurotransmitters and sterols, can be
viewed as a sulfate “escort” in the plasma. In (Samsel & Seneff, 2013),
it was argued that such carbon-ring-containing molecules are necessary
for safe sulfate transport, especially in the face of co-present
kosmotropes like glyphosate, in order to protect the blood from excess
viscosity during transport. Support for the concept that glyphosate gels
the blood comes from the observation that disseminated coagulation is a
characteristic feature of glyphosate poisoning (Zouaoui et al., 2013).
Since glyphosate disrupts sterol sulfation and it disrupts monoamine
neurotransmitter synthesis, in addition to its physical kosmotropic
feature, it can be anticipated that a chronic exposure to even a small
amount of glyphosate over the course of time will lead to a system-wide
deficiency in the supply of sulfate to the tissues. We believe that this
is the most important consequence of glyphosate's insidious slow
erosion of health.
An interesting consideration regarding a known link between celiac disease and hypothyroidism (Collins et al., 2012)
emerges when one considers that iodide is one of the few chaotropic
(structure breaking) anions available to biological systems: another
important one being nitrate, which is elevated in the urine in
association with celiac disease (Laurin et al., 2003).
It is intriguing that the conversion of T4 to T3 (the active form of
thyroid hormone) involves selenium as an essential cofactor.
Furthermore, iodide is released in the process, thus providing
chaotropic buffering in the blood serum. Therefore, impaired conversion
due to deficient selenium results in an inability to buffer this
significant chaotrope in the blood, despite the fact that chaotropic
buffering is likely desperately needed in the context of the kosmotropic
effects of glyphosate. While speculative, it is possible that the
autoimmune thyroid disease that develops in association with celiac
disease is a direct consequence of the inability to activate thyroid
hormone due to insufficient selenium. Indeed, celiac patients with
concurrent hypothyroidism require an elevated dose of levothyroxine (T4)
compared to non-celiac hypothyroid patients (Collins et al., 2012), which could be due to impaired activation to T3.
The
link between autoimmune (type 1) diabetes and autoimmune thyroiditis is
likely tied to deficiencies in selenoproteins leading to apoptosis.
Diabetic rats produce significantly less glomerular heparan sulfate in
the kidneys than controls, and this is associated with increased
albuminurea (Jaya et al., 1993).
However, children with type-1 diabetes and celiac disease excrete lower
levels of albumin than type-1 diabetic children without celiac disease,
suggesting a protective role for celiac disease (Gopee et al., 2013).
Wheat is a good source of tryptophan, so it is likely that
tryptophan-derived serotonin induces the symptoms of diarrhea and nausea
associated with wheat ingestion, but, at the same time, transports
available sulfate through the vasculature, to help maintain adequate
supplies of heparan sulfate to the glomerulus. Thus, the increased
metabolism of dietary tryptophan to serotonin observed in association
with celiac disease may help ameliorate the sulfate deficiency problem.
Glyphosate's interference with CYP enzymes links to impaired bile-acid
production in the liver, which in turn impairs sterol-based sulfate transport, placing a higher burden on serotonin for this task.
We
have argued here that kidney failure, a known risk factor in celiac
disease, is a consequence of depleted sulfate supplies to the kidneys.
An alarming increase in kidney failure in young male agricultural
workers in sugar cane fields in South America can be directly linked to
the recent increase in the practice of using Roundup to “ripen” the crop
just prior to the harvest. Furthermore, glyphosate's interference with
selenoprotein supply would lead to thyroid dysfunction, which greatly
increases risk to kidney disease. We propose here that glyphosate is the
key environmental factor contributing to this epidemic, but further
investigation is warranted.
While we have
covered a broad range of pathologies related to celiac disease in this
paper, and have shown how they can be explained by glyphosate exposure,
there are likely still other aspects of the disease and the connection
to glyphosate that we have omitted. For example, in a remarkable case
study (Barbosa, 2001),
a 54-year-old man who accidentally sprayed himself with glyphosate
developed skin lesions six hours later. More significantly, one month
later he exhibited symptoms of Parkinson's disease. Movement disorders
such as Parkinsonism are associated with gluten intolerance
(Baizabal-Carvallo, 2012). Figure 6
shows plots of glyphosate application to corn and soy alongside plots
of deaths due to Parkinson's disease. These and other connections will
be further explored in future research.
Deaths from Parkinson's disease (ICD G20 & 332.0) plotted against glyphosate use on corn & soy (R=0.9006, p≤5.063e-07) and % GE corn & soy planted (R=0.9676, p≤2.714e-06). Sources: USDA:NASS; CDC. (Figure courtesy ...
16 Conclusion
Celiac
disease is a complex and multifactorial condition associated with
gluten intolerance and a higher risk to thyroid disease, cancer and
kidney disease, and there is also an increased risk to infertility and
birth defects in children born to celiac mothers. While the principal
diagnostic is autoantibodies to tissue transglutaminase, celiac disease
is associated with a spectrum of other pathologies such as deficiencies
in iron, vitamin D3, molybdenum, selenium, and cobalamin, an overgrowth
of pathogens in the gut at the expense of beneficial biota, impaired
serotonin signaling, and increased synthesis of toxic metabolites like
p-Cresol and indole-3-acetic acid. In this paper, we have systematically
shown how all of these features of celiac disease can be explained by
glyphosate's known properties. These include (1) disrupting the
shikimate pathway, (2) altering the balance between pathogens and
beneficial biota in the gut, (3) chelating transition metals, as well as
sulfur and selenium, and (4) inhibiting cytochrome P450 enzymes. We
argue that a key system-wide pathology in celiac disease is impaired
sulfate supply to the tissues, and that this is also a key component of
glyphosate's toxicity to humans.
The
monitoring of glyphosate levels in food and in human urine and blood has
been inadequate. The common practice of desiccation and/or ripening
with glyphosate right before the harvest ensures that glyphosate
residues are present in our food supply. It is plausible that the recent
sharp increase of kidney failure in agricultural workers is tied to
glyphosate exposure. We urge governments globally to reexamine their
policy towards glyphosate and to introduce new legislation that would
restrict its usage.
Acknowledgements
The
authors would like to thank Nancy Swanson for her gracious effort in
the creation of the informative pictorial graphs included with the text.
Her statistical research for glyphosate usage and disease over time is
an invaluable contribution to our paper. Stephanie Seneff would also
like to personally thank Jennifer Moeny for her most informative
discussions concerning current associative prognosis, research and
trends in Celiac disease and gluten intolerance. This work was funded in
part by Quanta Computers, Taipei, Taiwan, under the auspices of the
Qmulus Project.
Disclosures: The authors have nothing to disclose.
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