Examining a Possible Link between Glyphosate
Exposure and Health Status among Racehorses
Stephanie Seneff l , Anthony Samsel 2 and Gregory Bennett 3
1. Computer Science and Artificial Intelligence Laboratory, MIT,
Cambridge MA 01890 USA. Email: [email protected]
2. Samsel Environmental and Public Health Services, Deerfield, NH
03037, USA. Email: [email protected]
3. ???
1 Introduction
The recent deaths of up to 11 young racehorses on the Del Mar, CA, race
track is cause for alarm. This is part of a much larger problem of failing
health among racehorses, as there is now general agreement that horses
today are suffering from more debilitating health issues than was the case
two or three decades ago. In a 2006 study investigating over 1000 horses,
veterinary problems were found in 62% of the two-year olds and 50% of
three-year olds [1]. The most commonly reported problems included sore
shins, inflammatory airway disease, joint problems, and fractures.
While it has been suggested that unreasonable performance demands
under harsh conditions and/or the overuse of certain drugs such as Lasix
may be contributing to this increase, we highly suspect a toxic chemical
exposure mainly from food sources as the primary cause of their overall
deteriorating health. In fact, we hypothesize that the pervasive herbicide,
Roundup®, may be a significant causal factor, as there is strong evidence
from the known toxicological effects of Roundup® to implicate a possible
causative role. If we succeed in showing a cause-and-effect relationship
between Roundup® and health status of racehorses, it will be good news,
because a straightforward solution is to switch racehorses to a 100%
certified organic diet. The higher food costs will be more than offset by
the reduced medical bills as well as the superior athletic performance of
the horses.
Glyphosate is the active ingredient in Roundup®. Although Monsanto, its
manufacturer, has claimed that glyphosate is nearly nontoxic to mammals,
much evidence from the independent research literature is proving
otherwise [2, 3, 4, 5, 6, 7]. Many of the conditions that racehorses suffer
from today can be explained by the known toxicological effects of
glyphosate. Perhaps the most troubling one is cardiac arrest following
arrhythmias at the conclusion of a race. This is remarkably similar to
cardiovascular effects of glyphosate on exposed rats in a recently
published study [8]. Reproductive issues are likely also in part attributable
to glyphosate exposure. Glyphosate's adverse effects on the male
reproductive system are well characterized [4]. Glyphosate has also been
shown to cause severe health problems, including congenital deformities
and failure to thrive, among piglets in Denmark [9].
A consideration of the standard diet of racehorses reveals some likely
sources of glyphosate exposure. Alfalfa [10, 11] and sugar beets (beet
pulp) [12] are among the short list of crops that have been engineered to
be glyphosate resistant. As a consequence, glyphosate application to
control weeds results in significant uptake by the crops. The use of
glyphosate has risen sharply over the past decade or more, as a
consequence of the widespread appearance of glyphosate-resistant weeds.
Very little monitoring has been conducted by the government, so there is
insufficient knowledge to date of the degree of exposure from food
sources. However, a recent study found glyphosate residues in several
samples of various brands of cat and dog food, including premium brands
[13].
In this research, we propose to systematically measure glyphosate levels
in the urine of a large number of racehorses, and to look for correlations
of high levels, if found, with health status. We also want to replace the
diet with organic alternatives, and to observe whether this results in health
improvements.
2 Evidence Linking Glyphosate to Health Issues
Racehorses suffer from multiple health problems. The most common
issues relate to fractures and other musculoskeletal injury [14] and
respiratory problems [15, 16]. Neurological, gastrointestinal, ophthalmic,
and reproductive problems, as well as infection, are also relatively
common. As in humans, there is a condition called "equine metabolic
syndrome" that parallels the human version of metabolic syndrome,
which is associated with obesity and diabetes in horses [17]. Laminitis is
a crippling condition often linked to insulin resistant diabetes [17, 18].
Diabetes in humans is associated with increased risk to osteoporosis and
fragility fractures [19]. In this section, we discuss several different health
issues facing racehorses and explain how glyphosate could be causal in
these conditions.
Glyphosate's toxicity arises due to multiple distinct physical and chemical
properties of this unusual synthetic molecule. In [7], arguments were
advanced that glyphosate's ability to strongly chelate multiple minerals
makes them unavailable to the microbiome, leading to an imbalance in
gut microbes and subsequent gastrointestinal disease. In fact, glyphosate
has been patented as an antimicrobial agent. Chronic idiopathic
inflammatory bowel disease is a relatively common condition in horses
today that was first observed in 1974 [20], which is when glyphosate was
first introduced on the market. Glyphosate also disrupts the activity of
cytochrome P450 (CYP) enzymes in the liver, which has multiple effects
on liver function including impairing the ability to detoxify multiple other
environmental toxic chemicals. Vitamin D is activated by CYP enzymes
in the liver and kidney, so deficient CYP activity could be causal in
vitamin D deficiency.
Glyphosate is an amino acid analogue of the coding amino acid, glycine,
and it likely derives much of its toxicity from its ability to disrupt
glycine's multiple roles in the body. Most significantly, it is highly likely
that glyphosate can substitute by mistake for glycine during protein
synthesis [21], and this ability would lead to an insidious accumulation of
glyphosate in multiple proteins throughout the tissues, causing grave
structural and functional damage and easily explaining the strong
correlations between glyphosate and the alarming rise we are observing
today in multiple diseases among humans.
2.1 Sudden Death
Multiple cases of sudden death during high profile horse race
competitions have alerted the general public to this serious health threat
for racehorses. Possible causes include rupture of an aortic aneurism and
arrhythmias leading to cardiac arrest. Both of these can easily be
explained by chronic exposure to glyphosate.
A recent paper by Gress et al. [5] involved exposing Sprague-Dawley
male rats to Roundup® and specifically addressing cardiovascular effects.
Roundup® caused conduction blocks, long QT syndrome, and
arrhythmias in the exposed rats. Interestingly, the effects were
substantially blocked through administration of ouabain, a drug known to
suppress the activity of the sodium-potassium pump.
Humans exposed to toxic levels of glyphosate through suicide attempts
also exhibit similar cardiovascular effects, including long QT syndrome,
atrioventricular conduction block, arrhythmias and cardiac arrest [22]. In
this study, patients who died were more likely to show a prolonged QT
interval. Long QT syndrome is also a feature of racehorses that is linked
to sudden death [23].
The sodium-potassium pump is tightly regulated. Multiple proteins are
involved in either suppressing the gain or triggering clearance of the
protein based on appropriate signaling cascades. We have discovered that
at least three of the proteins involving the pump contain highly conserved
glycine residues that could be disrupted by glyphosate. One of these,
phospholemman, is normally attached to the pump in the membrane, and
it suppresses its activity level by about a factor of two. Disruption of its
two highly conserved glycines by glyphosate will prevent it from
anchoring in the membrane, essentially disabling its function altogether
[24]. The second protein is a kinase which phosphorylates and inactivates phospholemman. Glyphosate's substitution for glycine in the active
site of the kinase can be predicted to increase its activity [21], thus
disabling phospholemman's suppression of the pump even when the
phospholemman is not itself contaminated with glyphosate. The third
protein is the glycine-rich ZNRF2, which controls the degradation of the
Na-K pump. Disruption of its conserved glycines will cause the pump to
linger longer than it should, thus exhausting ATP supplies and causing the
cell to reach a hyperpolarized state, with too much internal potassium and
too little internal sodium [25]. In the situation of a race horse at the
sudden cessation of movement at the end of a race, it can be predicted that
the pump will not be able to turn off sufficiently fast, the potassium levels
in the blood will decline sharply, and this will initiate the arrhythmias and
subsequent cardiac arrest. Marfan syndrome is a relatively common
genetic disease among humans that leads to a high risk for ruptured aorta,
particularly if they choose an athletic career [26, 27, 28, 29]. A wellknown case is the US Olympic volleyball star Flo Hyman, who died at the
age of 31 from a ruptured aorta [27]. The disease typically involves one of
a large number of mutations in the gene for the protein fibrillin, an elastic
fiber found in connective tissue. A study examining six distinct mutations,
all involving a substitution of a bulkier amino acid for an essential glycine
in fibrillin, showed that each of these mutations resulted in Marfan
syndrome and a strong risk of aortic rupture among multiple family
members sharing the gene [29] 1:Collagen, a dominant protein in
connective tissue, contains huge amounts of glycine.
About 25% of the amino acid residues in collagen are glycine molecules.
Osteogenesis imperfecta is a generalized disorder of connective tissue
characterized by fragile bones that are easily susceptibility to fracture.
Marini et al. have tabulated 832 distinct mutations in collagen linked to
osteogenesis imperfecta, and the overwhelming majority of these involve
point substitutions for glycine [30]. Therefore, it becomes evident that
glyphosate substitution for glycine in collagen can lead to a similar
defective condition. Random glyphosate substitutions for glycine in both
collagen and fibrillin during protein synthesis leads to a weakened
collagen matrix which is particularly dangerous in the aorta which faces
considerable stress under high pressure.
2.2 Botulism
Botulism is a serious threat to horses fed silage contaminated with
Clostridium botulinum [31, 32]. The condition is manifested by
neuromuscular paralysis and is often fatal. Enterococcus species thriving
in the gut can suppress the growth of pathogens such as Clostridium. In
vitro experiments have shown that glyphosate at low concentrations
inhibits the growth of Enterococcus facailis in cattle and horse feces,
which leads to increased risk to botulism due to Clostridium overgrowth
in the gut [33]. More generally, disruption in the gut microbiota is a major
potential risk of chronic exposure to environmental toxins, including
glyphosate [34].
2.3. Liver Disease
Diagnosis of liver disease in horses can be difficult because the clinical
signs are highly variable and often nonspecific [35]. Common causes of
liver disease in the horse include biliary obstruction secondary to
intestinal displacement or biliary stones [36], chronic active hepatitis and
fatty liver disease. Elevation in the serum level of gamma glutamyl
transpeptidase (GGT) is a good indicator of liver disease and is a strong
risk factor for multiple other diseases, including cardiovascular disease,
diabetes, metabolic syndrome (MetS), and all-cause mortality [37].
Increased GGT levels have been reported in young Thoroughbred
racehorses even without obvious liver dysfunction.
There has been a recent upward trend in the serum levels of GGT across
the human population in the past two decades, particularly in the United
States and Korea, two countries where glyphosate exposure is high [37].
GGT is an enzyme that breaks down glutathione, a tripeptide sequence
containing glycine, glutamate and cysteine. It is possible that glyphosate,
acting as a glycine analogue, is substituting for glycine in glutathione,
disrupting its function and necessitating clearance.
A postmortem case study of a nine-year-old Thoroughbred racehorse that
died of liver disease revealed a marked elevation in GGT levels, along
with a markedly enlarged liver (3.6% of body weight), hepatic lipidosis,
severely obstructed bile flow due to cholelithiasis and severe portal
fibrosis [35].
2.4 Musculoskeletal Problems
Glyphosate's ability to replace glycine in collagen could result in weaker
collagen and predispose to breakdown injuries of tendons and ligaments.
In addition, incorporation into the bone matrix may predispose to
fractures. Tissue sample collection of surgical procedures and post
mortem samples could be analyzed for the presence of glyphosate.
Glyphosate is also neurotoxic: glyphosate's known ability to chelate
minerals, especially cobalt and manganese [38], can lead to deficiencies
in blood and tissues. Chondroitin sulfate synthesis depends on manganese
and is critical for bone development. Furthermore, attachment of
chondroitin sulfate, heparan sulfate and keratan sulfate to collagen
depends on critical glycine residues that could be displaced by glyphosate
[30].
2.5 Pulmonary Disease
Exercise-induced pulmonary hemorrhage (EIPH) - bleeding that occurs
from the lungs during intense exercise — is a serious issue with race horses
that is believed to be related in part to the widespread practice of
administering furosemide (Lasix) [39]. However, glyphosate's ability to
interfere with the function of CYP (cytochrome p450) enzymes,
especially endothelial nitric oxide synthase (eNOS) [7], could also be a
factor in EIPH by its expected adverse effects on vascular resistance and
blood pressure regulation. Furthermore, the potential of glyphosate to
substitute for glycine in collagen and elastin could weaken the vascularrespiratory interface at the alveoli, disturbing the elasticity of the lung and
predisposing to EIPH. Autopsy studies to characterize pathology
specimens of lung may reveal a weakened lung tissue identified by the
replacement of collagen with a more inelastic protein structure, and by a
deficiency in attached sulfated proteoglycans such as heparan sulfate. By
enzymatic analyses of lung tissue, glyphosate residues could possibly be
discovered [40].
Infectious respiratory disease is common in racehorses, particularly young
Thoroughbred racehorses [41]. Chronic obstructive pulmonary disease
(COPD) is also a common disease of horses, not especially seen in young
thoroughbred racehorses, but presented more often in older horses. As
glyphosate is able to incorporate in place of glycine in collagen and
elastin, it could lead to some of the clinical signs of COPD.
2.6 Retinoic Acid Overexpression
A seminal study involving exposing frog embryos to glyphosate revealed
considerable disruption of development consistent with excess exposure
to retinoic acid [3]. This is plausibly due in part to glyphosate's known
effect to suppress CYP enzyme activity [42], since retinoic acid is
metabolized by CYP enzymes. A retinoic acid analogue used to treat acne,
Tretinoin, has many side effects that correspond to some of the known
common health issues in racehorses [43, 44]. Respiratory side effects that
signify retinoic acid syndrome include upper respiratory tract disorders,
dyspnea, respiratory insufficiency, pleural effusion, pneumonia, rales and
expiratory wheezing. Excessive retinoic acid also has multiple effects on
the cardiovascular system, including arrhythmias, hypotension, cardiac
arrest, pericarditis, pulmonary hypertension, and enlarged heart.
Intracranial abscesses due to intracranial hypertension are relatively
common among horses, and are often fatal [45]. A causal factor could be
glyphosate's induction of excessive levels of retinoic acid. Retinoic acid
treatment for leukemia has caused intracranial hypertension in both
children [46] and adults [47].
2.7 Laminitis and Insulin Resistance
Laminitis (also known as founder) results from a failure of the hoof
lamellar-distal phalangeal attachment apparatus, and it is a significant
cause of lameness in horses. While the exact causal mechanism remains
unknown, laminitis is clearly linked to diabetes and insulin resistance in
horses [18]. In fact, a controlled experiment conclusively demonstrated
that insulin and glucose infusion can induce laminitis in non-insulin
resistant horses. Equine metabolic syndrome is a growing problem in
horses and is directly tied to both insulin resistance and laminitis [17].
Metabolic syndrome and associated diabetes in humans has reached
epidemic proportions in the modern world [48], and the rise in diabetes
incidence in the US is strongly correlated with the rise in glyphosate
usage on core crops [49]. In [21], it was shown that glycine plays an
essential role in the insulin receptor's ability to bind to the plasma
membrane. Glyphosate substitution for glycine in the insulin receptor
would therefore directly lead to insulin resistance.
3 Research Plan
Based on initial samples of the racehorse feed collected and analyzed for
the presence of glyphosate, it was determined that three commonly used
feeds have glyphosate residues present. The initial feed collection study
was based on clinical signs of high liver enzymes (particularly GGT),
weight loss and inappetence in a racing thoroughbred filly. Upon
cessation of feeding the tested feed, the filly showed marked
improvement in appetite within five days. Serial blood analysis showed
significant improvement (lowering) of GGT within thirty days, with
return to normal values within ninety days.
Based on evidence presented in this paper, we propose a more thorough
study analyzing feed samples and blood/urine samples from a larger
population of racehorses. Introduction of organic feeds in selected horses
would be beneficial to test the clearance of glyphosate from blood/urine
samples and to see whether symptoms improve following the switch to an
organic diet.
Due to glyphosate's ability to substitute for glycine in many proteins,
especially collagen [21], further investigation of select tissue may reveal a
weakened collagen structure, which could further potentially lead to MSK
injuries.
Studies into necropsy specimen tissues may reveal more information
regarding damaged structural integrity of collagen tissue, which could
influence breakdown injury and cardiovascular events. We will also
subject tissue specimens to analysis for glyphosate contamination, both
before and after extensive enzymatic proteolysis, in order to assess
whether glyphosate is embedded in the peptides present in the tissues.
4 Conclusion
As veterinarians and researchers, we have an obligation to protect the
welfare and health of animals we care for. Any potential sources of feeds,
supplements or pharmaceuticals that could adversely affect our patients
should be vigorously investigated. Much data exists in humans and other
animal species that indicate that glyphosate could adversely affect many
organ systems in the horse. Further investigation is warranted based on
finding glyphosate in very high amounts in commercial horse feeds.
Toxicity is magnified many times as glyphosate is formulated with
additional adjuvants that enhance its toxicity [50].0As racehorses are
stabled indoors more frequently and are exposed less to sunlight, vitamin
D deficiency could result. Racehorses that train in very early sets in the
morning may get very little sun exposure especially in the winter months
in the northeast U.S.A. Reduced sun exposure could also cause reduced
cholesterol and sulfate metabolism and transport, and negatively affect
overall health [51].
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