Endocrine disruptors
"Some of the most important publications by scientific teams supported by CRIIGEN or by CRIIGEN members who have participated in them.
Traditionally, when a scientific study is cited, only the name of the first author is given. Exceptionally, all authors are cited to thank them for their efforts, cooperation and support of CRIIGEN.
(Authors who are members of CRIIGEN are underlined)
2017
Toxicity of formulants and heavy metals in glyphosate-based herbicides and other pesticides. N Defarge, J Spiroux de Vendômois, G E Séralini. Toxicol Rep. 2017. Doi : 10.1016/j.toxrep.2017.12.
" Toxicity of formulants and heavy metals in glyphosate herbicides and other pesticides ".
The main pesticides used worldwide are glyphosate-based herbicides (GBH), and their toxicity is highly controversial. To understand their mode of action, the comparative herbicidal and toxicological effects of glyphosate (G) alone and 14 of its formulations were studied in this work, as a model for the pesticides...
GBHs are water mixtures, generally with 36% to 48% G claimed as the active ingredient. As with other pesticides, 10-20% of GBH is made up of chemicals. We had previously identified these by mass spectrometry and found that they were mainly families of petroleum-based oxidized molecules, such as POEA, and other contaminants. We exposed plants and human cells to the components of formulations, both mixed and separated, and measured toxicity and human cellular endocrine disruption below the experimentally measured threshold of direct toxicity. Contrary to popular opinion, G was only slightly toxic to plants at the dilutions recommended for agricultural use. In the short term, the strong herbicidal and toxic properties of its formulations were exerted by the POEA family of formulants alone. The toxic effects and endocrine-disrupting properties of the formulations were mainly due to the formulants and not to G. In this work, we also identified by mass spectrometry the heavy metals arsenic, chromium, cobalt, lead and nickel, known to be toxic. and endocrine disruptors, as contaminants in 22 pesticides, 11 of them G-based. This could also explain some of the adverse effects of the pesticides. In chronic in vivo regulatory experiments used to establish acceptable daily doses of pesticides, G or other active ingredients reported in pesticides are assessed alone, without the formulants. In the light of these new data, this assessment method appears insufficient to guarantee safety. Taken together, these results shed new light on the toxicity of these major herbicides and of pesticides in general.
2016
Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels. Nicolas Defarge, Eszter Takács , Verónica Laura Lozano , Robin Mesnage, Joël Spiroux de Vendômois, Gilles-Eric Séralini, András Székács. Int J Environ Res Public Health. 2016. Doi: 10.3390/ijerph13030264.
" Co-formulants in glyphosate-based herbicides disrupt aromatase activity in human cells below toxic levels ".
Pesticide formulations contain declared active ingredients and coformulants presented as inert, confidential compounds. We tested the endocrine disruption of coformulants in six glyphosate-based herbicides (GBH), the most widely used pesticides in the world.
All co-formulants and formulations were comparatively cytotoxic well below the 1% agricultural dilution (18 to 2,000-fold for co-formulants, 8 to 141-fold for formulations), and not the declared active ingredient, glyphosate (G), alone. The endocrine-disrupting effects of all these compounds were measured on the activity of aromatase, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was reduced both by the coformulants alone (polyethoxylated tallow amine-POEA and alkyl polyglucoside-APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G only exerted an effect at 1/3 of the agricultural dilution. It was shown for the first time that endocrine disruption caused by GBH could be due not only to the declared active ingredient, but also to co-formulants. These results could explain many in vivo results with GBH not observed with G alone; moreover, they call into question the relevance of the Acceptable Daily Intake (ADI) value for GBH exposures, currently calculated from toxicity tests on the declared active ingredient alone.
2009
Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines. Céline Gasnier, Coralie Dumont, Nora Benachour, Emilie Clair, Marie-Christine Chagnon, Gilles-Eric Séralini. Toxicology. 2009 doi: 10.1016/j.tox.2009.06.006.
" Glyphosate-based herbicides are toxic and endocrine disruptors of human cell lines ".
2007
Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination. Nora Benachour, Safa MoslemiHerbert Sipahutar, Gilles-Eric Seralini. Toxicology and Applied Pharmacology (2007). doi.org/10.1016/j.taap.2007.03.033
" Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disruptors alone and in combination ".
Xenobiotics can cause long-term adverse effects in humans, particularly at the embryonic level, raising questions about their exposure levels, combined effects and crucial endpoints. We focused on possible interactions between xenobiotic endocrine disruptors, cell viability and androgen metabolism.
Thus, we tested aroclor 1254 (A1254), atrazine (AZ), o,p′-DDT, vinclozoline (VZ), p,p′-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributyline oxide (TBTO) and diethylstilbestrol (DES) for cell toxicity against human embryonic cells and activity against cellular aromatase, but also on placental microsomes and purified equine enzyme. Cell viability was affected within 24 h by all xenobiotics with a threshold at 50 µM (except TBTO and DES, threshold 10 µM), and aromatase was inhibited at non-toxic doses. In combination, a synergy was observed, reducing toxicity threshold values to 4-10 μM and aromatase activity by 50% in some cases. In placental microsomes, the most active xenobiotics rapidly inhibit microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposure to low doses in cells generally results in a 50-fold increase in aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, notably chlordecone, DDT and DDE, and low-level chronic exposures can also affect cellular signalling mechanisms. This new information on the mechanism of action of these xenobiotics will help improve molecular design to provide safer compounds for use in the (human) environment.
Metals
2017
Toxicity of formulants and heavy metals in glyphosate-based herbicides and other pesticides. N Defarge, J Spiroux de Vendômois, G E Séralini. Toxicol Rep. 2017. Doi : 10.1016/j.toxrep.2017.12.
" Toxicity of formulants and heavy metals in glyphosate herbicides and other pesticides ".
The main pesticides used worldwide are glyphosate-based herbicides (GBH), and their toxicity is highly controversial. To understand their mode of action, the comparative herbicidal and toxicological effects of glyphosate (G) alone and 14 of its formulations were studied in this work, as a model for the pesticides...
GBHs are water mixtures, generally with 36% to 48% G claimed as the active ingredient. As with other pesticides, 10-20% of GBH is made up of chemicals. We had previously identified these by mass spectrometry and found that they were mainly families of petroleum-based oxidized molecules, such as POEA, and other contaminants. We exposed plants and human cells to the components of formulations, both mixed and separated, and measured toxicity and human cellular endocrine disruption below the experimentally measured threshold of direct toxicity. Contrary to popular opinion, G was only slightly toxic to plants at the dilutions recommended for agricultural use. In the short term, the strong herbicidal and toxic properties of its formulations were exerted by the POEA family of formulants alone. The toxic effects and endocrine-disrupting properties of the formulations were mainly due to the formulants and not to G. In this work, we also identified by mass spectrometry the heavy metals arsenic, chromium, cobalt, lead and nickel, known to be toxic. and endocrine disruptors, as contaminants in 22 pesticides, 11 of them G-based. This could also explain some of the adverse effects of the pesticides. In chronic in vivo regulatory experiments used to establish acceptable daily doses of pesticides, G or other active ingredients reported in pesticides are assessed alone, without the formulants. In the light of these new data, this assessment method appears insufficient to guarantee safety. Taken together, these results shed new light on the toxicity of these major herbicides and of pesticides in general.
2015
Mercurial exposure of residents of Santarém and Oriximiná cities (Pará, Brazil) through fish consumption. Jean-Paul Bourdineaud, Gilles Durrieu, Sandra Layse Ferreira Sarrazin, Wânia Cristina Rodrigues da Silva, Rosa Helena Veras Mourão, Ricardo Bezerra de Oliveira. Environ Sci Pollut Res Int. 2015. Doi: 10.1007/s11356-015-4502-y.
" Mercury exposure of residents of the cities of Santarém and Oriximiná (Pará, Brazil) through fish consumption ".
A survey of mercury exposure in Santarém and Oriximiná showed differential mercury impregnation between men and women. In both cities, mean hair mercury concentrations were 1.5 ± 0.5 (90th and 95th percentiles: 2.8 and 4.3) and 2.52 ± 0.09 μg g Hg/g (90th and 95th percentiles: 4.7 and 8.1) for women and men respectively. Mercury contamination appears to be significantly correlated with the daily amount of fish consumed...
The carnivorous species pescada branca (Plagioscion squamosissimus) and apapá (Pellona castelnaeana) and the non-carnivorous species pacú (Mylossoma duriventre) and aracú (Schizodon fasciatus) were consumed by 22, 19, 55 and 25% respectively, and the mean mercury content concentrations in fish flesh were 1.44 ± 0.11, 1.66 ± 0.19, 0.48 ± 0.09 and 0.49 ± 0.06 μg/g dry weight respectively. Men over 35 were significantly more contaminated than those under 35. Mean concentrations in men's hair were 5.20 ± 1.25 and 1.50 ± 0.22 μg/g, respectively for those over and under 35 years of age. The probability of women of childbearing age in both cities having a hair mercury concentration greater than 1 μg Hg/g (corresponding to the US Environmental Protection Agency reference dose) was equal to 0.30 (95% confidence interval 0.24 to 0.36). The probability of hair mercury concentration above the lowest observable adverse effect level (LOAEL) (0.3 μg Hg/g) was equal to 0.79 (95% confidence interval: 0.73-0.86).
Autism study
2019
Autism-modifying therapy based on the promotion of a brain enzyme: An introductory case-report. Dominique G. Béroule. AIMS Molecular Science, 6 (3): 52-72. DOI: 10.3934/molsci.2019.3.52
" Autism-modifying therapy based on brain enzyme promotion: about an introductory case."
An interdisciplinary study of autism has led to the questioning of the relatively low degradation of synaptic serotonin, a molecule involved in brain development. It is hypothesized that the resulting metabolic imbalance of monoamine neurotransmitters prevents the encoding of memory across sleep stages, resulting in the construction of aberrant neuronal structures linked to autistic symptoms...
... A drug can be derived from this theoretical approach, with the aim of regulating the neuromodulation by which appropriate neuronal networks can begin to develop over those that are degraded. The anticonvulsant Valproate was prescribed here for its contribution to the promotion of a relevant brain enzyme known as monoamine oxidase A (MAOA). While case studies typically focus on a subset of symptoms for less than three months in mild-to-moderate autism, the evolution of each autistic symptom was observed over a year in an 11-year-old boy with severe autism. A rapid improvement in sleep, followed by an increase in visual exploration, preceded positive changes in the main symptoms perceptible nine months later, but still hampered by bouts of hyperactivity. Complementary treatment with the psychostimulant methylphenidate then increased attention span without interfering with valproate. Such a combination of MAOA inducer and psychostimulant ultimately favored the gradual acquisition of social conditioning, without completely erasing the bad habits stemming from ten years of autism. Because it is restricted to a disease-modifying action, this dual therapy relies on accompanying educational support, as we have learned from its exploratory follow-up. Other knowledge focuses on specific biomarkers and functional polymorphisms of relevant gene promoters, with the aim of guiding future clinical trials.
2018
Offline encoding impaired by epigenetic regulations of monoamines in the guided propagation model of autism. Dominique G Béroule. BMC Neurosci. 2018. Doi: 10.1186/s12868-018-0477-1.
" Offline coding altered by epigenetic monoamine regulations in the guided propagation model of autism ".
Commentary: This theoretical study shows that the various manifestations of autism may originate in a specific disruption of critical periods of brain development in the foetus. According to this approach, a molecule ingested by a pregnant woman invades the regulatory mechanisms that determine gene expression (epigenetics) involved in the chemical control of the central nervous system. This is a relatively comforting prospect for parents of autistic children, since no hereditary defect, in the form of genetic mutations, would be decisive in the genesis of this pathology.
Environmental factors can modify gene expression, particularly those involved in neurotransmitter metabolism. By taking into account the controlling role of monoamine neurotransmitters, the Guided Propagation (GP) memory model could contribute to studying the consequences of neuromodulation disorders on developmental disorders such as autism...
... A prenatal transient excess of the enzyme "monoamine oxidase A" is hypothesized here to trigger persistent epigenetic regulations that would induce unbalanced synaptic monoamine metabolisms. When imported into the "offline" coding cycles of a GP model, the resulting "serotonin noise" leads to aberrant memory structures that may be linked to autism symptoms.
Results: In computational experiments, different levels of decoupling between monoamine representations correlate with the amount of altered GP modules, the severity of irrelevant connections, as well as network proliferation. Two types of faulty connections are respectively hypothesized to underlie autistic traits, namely repetitive behavior and perceptual hypersensitivity. In addition to computer modeling, a genetic family tree shows how the sex ratio of autism can result from combinations of pharmacological and epigenetic features.
Conclusions: These results suggest that the current rise in autism is favored by three possible sources of biological masking: (1) during sleep, when cyclic variations in monoamines may undergo disrupted enzymatic activities; (2) through generations of "healthy carriers" protected by X chromosome inactivation and a specific genetic variant ; (3) early in life, as long as brain development relies on pools of neurons born when transient enzyme excess and its persistent epigenetic regulation overlap, and as long as monoamine oxidase type B has no significant impact on dopamine. A disease-modifying therapy may be derived from this study, which implies that relevant biomarkers are first monitored over several months of clinical trials.