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ISIS Report 19/03/14
Glyphosate/Roundup & Human Male Infertility
Steep decline in human male sperm count concomitant with
rise in testicular germ cell cancer, congenital malformations of the male
reproductive tract and drop in serum testosterone levels, all pointing towards increasing
exposure to glyphosate/Roundup herbicides during the past decades, now
corroborated by lab findings Dr Mae-Wan
“The infertility timebomb: are men facing extinction?”
The headline of a newspaper article published in 2010  refers
to findings from decades of research carried out by Niels Shakkebaek, a
professor at University of Copenhagen. Male infertility has been rising sharply
in industrialized countries worldwide, one in five healthy men between the ages
of 18 and 25 produce abnormal sperm counts. The problems start in the womb,
says Dr. Gillian Lockwood, medical director of Midland Fertility Services in
the UK. Testis development begins in the growing foetus. Factors blamed include
too much beef in the diet rich in polycyclic aromatics, obesity during
pregnancy, exposure to smoke, pesticides, traffic fumes, plastics and even
Shakkebaek first highlighted the
issue during a mini symposium at the European Medical Research Councils plenary
meeting in Strasbourg in 2009. Semen quality has been declining in the past
half century. In men without fertility problems, average sperm count dropped
from 113 x 106 to 66 x 106/ml. About 20 % of young men in
various European countries have sperm counts below the WHO (World Health
Organization) reference level of 2o m/ml, and 40 % of have levels below 40 m/ml
associated with prolonging the time to pregnancy . Concomitantly, the demand
for assisted reproductive technology (ART) is growing. In Denmark, more than 7
% of all children born in 2007 were conceived using ART.
There are geographical
differences in semen quality. Finnish men have 35 % higher sperm counts than
Danish men, while Scottish and French sperm counts are in between. Japanese
sperm counts are as low as those of the Danes, and Singapore men have even
lower sperm counts.
The trend in semen quality has implications
for health in general, as men with poor semen quality seem to have increased
mortality rates and shorter life expectancy. Infertility is also closely linked
to several dysfunctions and abnormalities of male reproductive organs that have
been rising concomitantly with infertility.
Infertility trend associated with testicular germ cell
cancer, congenital malformations & low testosterone
Testicular germ cell cancer (TGC) is the commonest cancer in
young men in many countries, associated with impaired semen quality and lower
fertility rates even prior to cancer development. The incidence of TGC has been
increasing over the past 40 to 50 years in the majority of industrialized
countries coincidentally with the declining trend in semen quality. TGC is initiated
during foetal development. The regional differences in TGC incidence in Europe
follow the same pattern as observed for semen quality.
Congenital malformations of the male
reproductive tract – undescended testis and incomplete fusion of the urethral
folds that form the penis – are among the most frequent congenital
malformations in human males. These two abnormalities share common risk
factors, both associated with reduced fertility; the first malformation is also
associated with poor semen quality and considerably increased risk of TGC.
Incidences of these malformations appear to have been increasing in the Western
world over recent decades.
Testosterone, the male hormone, is the major
driver of male reproductive development and function. Suppression of its levels
within the adult testis shuts down spermatogenesis and induces infertility. Studies
of men with idiopathic infertility – for which the cause is unknown - and low
sperm counts often show evidence of abnormal Leydig cells, which produce
testosterone in the testis.
incidences of TGC and congenital reproductive tract malformations have been
going up coincidentally with a downward trend in semen quality and testosterone
levels (although there are only data for the latter in Denmark). These
disorders share common risk factors and are risk factors for one another.
Consequently, it has been proposed that the conditions collectively may
represent a syndrome - a testicular dysgenesis syndrome (TDS) - caused by a
common underlying causal factor, which is either a change in lifestyle or an
environmental toxin, especially endocrine disrupting chemicals such as
pesticides. Notably, the review published by the European Science Foundation (an
official body that coordinates international research programmes in Europe)
fails to mention glyphosate explicitly, even though its use has been rising
most rapidly among pesticides in Europe and in the rest of the world since the
1980s to 1990s.
Age-independent testosterone decline reflects rise in
glyphosate use with GM crops
In America, there has been a substantial age-independent
decline in testosterone that does not appear attributable to observed changes
in explanatory factors including health status and lifestyle characteristics
such as smoking and obesity. The estimated declines were larger than the cross
sectional declines typically associated with age, as shown in Figure 1 .
Age-independent decline in serum testosterone in America
The data are from randomly
selected men living in greater Boston, Massachusetts in the United States, not
connected with studies on infertility but with aging in general, as
considerable loss of serum testosterone is thought to be a mark of male aging.
It is notable that the steep
decline in testosterone levels began just after the introduction of genetically
modified (GM) crops in 1994 with concomitant increase in glyphosate herbicides
use on glyphosate tolerant GM crops. A comprehensive review article has blamed
glyphosate for “most of the diseases and conditions associated with a Western
diet” including infertility , although the precise mode of action, at least
in the case of infertility, remains unclear.
Roundup more damaging than
There is already evidence that
glyphosate is an endocrine disrupting chemical (see later), but the extent of
the problem is far greater than it appears. Different glyphosate formulations
vary in toxicity, mainly because some of them contain adjuvants that are either
toxic by themselves, or else exert synergistic effects with glyphosate. It has
long been known that Monsanto’s formulation Roundup, the most widely used
glyphosate herbicide, is far more damaging than glyphosate itself (reviewed in
GMOs Now, ISIS special report).
Séralini and colleagues at University of Caen in France clearly demonstrated
that POEA (polyethoxylated tallowamine, a major adjuvant surfactant in Roundup)
alone was by far the most cytotoxic for several human cell types, at
concentrations a hundredth to ten-thousandth that of glyphosate itself and
other formulations without POEA . Another study from the same laboratory also
showed that Roundup exposure damages testosterone producing Leydig cells from
mature rat testis at concentrations a tenth of agricultural use and beginning 1
hour after exposure . Within 24-48 h, the same formulation was toxic to
other cells inducing cell death, in contrast to glyphosate alone, which is only
toxic to Sertoli cells (feeder cells for germ cells). At 48 h, Roundup induces
apoptosis (programmed cell death involving DNA fragmentation) in germ cells and
in Sertoli/germ cells co-culture. At the very low, non-toxic concentration of 1
ppm, both Roundup and glyphosate decreased testosterone level by 35 %. These
experiments expose a major inadequacy in the regulatory regime, which still
regards POEA in Roundup as an inert adjuvant for which no risk assessment is
A recent laboratory
experiment shows that Roundup has direct, acute impacts on the mammalian testis
at levels of exposure orders of magnitude below recommended agricultural
Acute Roundup exposure at very low concentrations kills
cells in the immature testis
The Brazilian research team led by Ariane Zamoner at the
Federal University of Santa Catarina in Florianópolis, and Federal University
of Rio Grande do Sul in Porto Alegre, are well aware of the increased toxicity
of Roundup compared with glyphosate, and were prompted to investigate the
effects of Roundup by the high prevalence of
reproductive dysfunction among agricultural workers occupationally exposed to the
herbicide. They looked at concentrations of Roundup 2 to 3 orders of
magnitude below the 10 000 to 20 000 ppm (10-20g/L) used in agriculture, which
is quite realistic in terms of exposure levels for agricultural workers and
members of the general public close to or within the spraying range .
The researchers found that brief
exposure to Roundup at 36 ppm (0.036 g/L) for 30 minutes was sufficient to
induce oxidative stress (a failure of energy metabolism, see later) and
activate multiple stress-response pathways leading to cell death in the pre-puberty
The team concluded : “Altogether, the Ca2+-mediated disturbances by
glyphosate-Roundup in rat testis cells around 36 ppm, could contribute to the
reproductive effects observed in male agricultural workers exposed to this
pesticide at prepubertal age.”
Detailed mechanisms of action identified
The team found that Roundup increases intracellular Ca2+
concentration by opening L-type -voltage-dependent Ca2+ channels –
thereby allowing Ca2+ to enter the cells - as well as targeting the
endoplasmic reticulum IP3 (inositol triphosphate) and ryanodine receptors (both
Ca2+ release channels), leading to Ca2+ release and overload
within the cells, setting off cell death. The mechanisms involved were inferred
from experiments with specific inhibitors that cancelled out the effect of
Roundup as well as Ca2+ influx; and confirmed by the increase in
radioactive tracer 45Ca2+ uptake by testis incubated with
Roundup at 36 ppm. These events were prevented by the antioxidants Trolox and
ascorbic acid, which counteract the reactive oxygen species (see below)
responsible for the oxidative stress. Activated
protein kinase C, phosphatidylinositol 3-kinase, and the mitogen-activated
protein kinases such as ERK1/2 and p38MAPK all play a role in eliciting Ca2+ influx and cell death.
also decreases the levels of reduced glutathione (GSH, the tissue’s own
antioxidant) as consistent with oxidative stress, and increases the amounts of
thiobarbituric acid reactive species (TBARS) and protein carbonyls, which are
signs of oxidative damage from reactive oxygen species to lipids and proteins
respectively. Exposure to Roundup stimulates the activities of a whole
collection of enzymes supporting the down-regulation of GSH levels.
The research team looked at acute
Roundup exposure of both whole immature Wistar rat testis and isolated Sertoli
cells in culture; and the findings were very similar in the two systems.
on their experimental results, the team propose that Roundup toxicity is due to
Ca2+ overload, resulting
in cell signalling fault, a stress response and/or defence against depleted
antioxidant, all contributing to the death of Sertoli cells, thereby impacting on
new findings are consistent with the well-known involvement of Ca2+
in cell death from oxidative stress. Oxidative stress causes Ca2+
influx into the cytoplasm from the extracellular environment and from the
endoplasmic reticulum . Rising Ca2+ concentration in the
cytoplasm in turn causes Ca2+influx into the mitochondria and
nuclei. In the mitochondria, Ca2+ accelerates the disruption of
normal oxidative metabolism leading to necrotic cell death. In nuclei, Ca2+
modulates gene transcription and nucleases that control apoptosis (programmed
cell death that involves fragmentation of DNA).
There is already evidence that
glyphosate may act as an endocrine disruptor for both males and females by
altering aromatase activity, oestrogen regulated genes, and testosterone levels
in rats . But Roundup acts via different mechanisms. Roundup exposure
during pregnancy and lactation at a level that did not induce maternal toxicity
in Wistar rats nevertheless induced adverse reproductive effects in male
offspring, including decreased daily sperm production during adulthood,
increase in abnormal sperms, and low testosterone serum level at puberty. In
exposed female offspring, only a delay in vaginal canal opening was observed .
Oxidative stress and
endocrine disrupting effects specific to Roundup
The key to understanding the action of Roundup on male
infertility is the reactive oxygen species (ROS) generated in oxidative stress
(see [12, 13] The Body Does Burn
Water and Living
with Oxygen, SiS 43). Not only are ROS implicated in
practically every chronic human disease including cancer  (Cancer
a Redox Disease, SiS 54), but also play an essential role in the
pathogenesis of many reproductive processes as detailed in a review published
in 2003 . In male-factor infertility, oxidative stress attacks the lipids
of the sperm plasma membrane and the integrity of DNA in the sperm nucleus. In
addition, ROS induce DNA damage, accelerate germ cell death and decrease sperm
counts, thereby contributing to male infertility.
ROS is so
closely linked to male infertility that infertile males generating high levels
of ROS are 7 times less likely to initiate a pregnancy compared with those with
low levels of ROS. A meta-analysis demonstrated that ROS levels were
significantly correlated with the fertilization rate in couples undergoing in
vitro fertilization .
Ashok Agarwal at the Center for
Advanced Research in Human Reproduction, Infertility and Sexual Function,
Cleveland Ohio in the United States led a retrospective study
on 132 male factor infertility (MFI) patients (failure to initiate pregnancy
with fertile partner after one year of unprotected sex) consisting of 24 with
all normal sperm parameters, 38 with all abnormal parameter and the rest with 1
or more abnormal parameters . They found that the 34 normal healthy donors (controls)
had significantly higher sperm concentrations, motility and morphology compared
with all MFI patients. There was a significant association between MFI and ROS
with odds ratio of 4.25, independently of sperm parameters and age. They
concluded that high ROS is an independent marker of MFI, irrespective of
whether these patients have normal or abnormal semen parameters. They
proposed that ROS measurement should be included a part of idiopathic
infertility evaluation, and treatment with antioxidants may be beneficial for
ROS are generated as intermediates in the
central metabolic process whereby oxygen-breathing organisms obtain energy to
fuel all their activities. The energy metabolism takes place in the
mitochondria, the tiny membranous powerhouses within cells where fragments from
the breakdown of glucose are oxidized ultimately into carbon dioxide and water.
It involves a tightly coupled process of oxidative phosphorylation in
which electrons and protons are extracted from the chemical fragments, with
electrons transported down the electron transport chain and protons
transported up the proton gradient, so that their energy can be tapped to
make ATP (adenosine triphosphate, the universal energy intermediate of the
body) (for a good summary of the entire process see Chapters 21 and 22 of  Living_Rainbow_H2O,
ISIS publication). During this tightly coupled process, ROS are generated as partially
oxidized intermediates . Consequently, disturbances that uncouple oxidative
phosphorylation lead to a failure of oxidation and release the partially
oxidized and damaging ROS intermediates into the cell, resulting
in oxidative stress.
It is very likely
that the primary target of Roundup, especially its POEA surfactant, is the
mitochondria, which play a key role in the development of sperm cells and sperm
motility . In addition, male infertility could arise from ROS damages to
at University of Trás-os-Montes, Real, in Portugal compared the effects of
Roundup with glyphosate on isolated rat liver mitochondria  and found
dramatic differences. Roundup collapses the transmembrane potential of the
mitochondria and uncouples oxidative phosphorylation, depressing the rates of
oxidation, with effects starting at 0.5 mM (7.5 ppm). These effects are most
likely due to non-specific permeation of the mitochondrial membrane by Roundup
or its adjuvant POEA. In addition, Roundup specifically inhibited succinate
dehydrogenase, succinate cytochrome c reductase, and ATP synthase and ATPase,
key enzymes in oxidative phosphorylation. Glyphosate, on the other hand, does
not have any significant effects on the function of mitochondria up to the
highest concentration used, 15 mM (253.5 ppm).
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There are 5 comments on this article so far. Add your comment
|Jane Peters Comment left 19th March 2014 16:04:07|
We should est like Adam and Eve ate, organic. Pulling weeds and composting them is safer than spraying everything including our food with poison.
|Rory Short Comment left 19th March 2014 16:04:37|
This is frightening, and, it is all happening, and continues to happen, because the manufacturers make money out of the chemicals involved.
|Todd Millions Comment left 22nd March 2014 21:09:51|
So russian rat research on gm glyphosate drenched soy from2002 is confirmed on the male side.Sudden male breast development amounst burbon drinkers in the USA 10 years earlier should have being a-tell.As well as the GM crops,and residue-the practice of spraying non gm(organic) crops with roundup has become widespread and legal(not tested)-as a dessicant.So not a herbiside application.As well factory feedlot wennies and thier evil help mates,are cutting back on- kill the steers with antibiotic laced feed,and replacing it with glyposate drenched feed.They can claim reduced antibiotic levels,and have the same inflamation caused 'weight gain'The tainted feed produces.Of course ag/tox and health/pharmawhore Canada are right on top of this case.Not!
|LESLIE THOMPSON F.I.S.T. Comment left 23rd March 2014 18:06:16|
And it is all down to money
the money Monsanto & others are making from G M foods
CAnt we stop them somehow?
|Pat Kozowyk Comment left 25th March 2014 18:06:28|
I don't have references to any studies, but an organic poultry producer told me that the sharp rise in price for conventionally produced live chicks (for poultry farm production) is due to the sharp decline in poultry fertility. A couple of small scale organic producers that I know of, are rearing their own chicks. I would like to see a study comparing fertility rates. Very likely roundup, etc. in the conventional feed causing fertility problems in poultry as well.