Genotoxicity and other research
"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)
Genotoxicity / Epigenetics
2022
Comparative Toxicogenomics of Glyphosate and Roundup Herbicides by Mammalian Stem Cell-Based Genotoxicity Assays and Molecular Profiling in Sprague-Dawley Rats. Robin MesnageMariam Ibragim, Daniele Mandrioli, Laura Falcioni, Eva Tibaldi, Fiorella Belpoggi, Inger Brandsma, Emma Bourne, Emanuel Savage, Charles A Mein, Michael N Antoniou. Toxicol Sci. 2022. Doi: 10.1093/toxsci/kfab143.
Comparative toxicogenomics of glyphosate and Roundup herbicides using mammalian stem cell-based genotoxicity assays and molecular profiling in Sprague-Dawley rats.
Whether glyphosate-based herbicides (GBHs) are more potent than glyphosate alone in activating the cellular mechanisms underlying carcinogenesis remains controversial. Since GBHs are more cytotoxic than glyphosate, we thought they might also be more capable of activating carcinogenic pathways...
We tested this hypothesis by comparing the effects of glyphosate with those of Roundup GBH in vitro and in vivo. Firstly, glyphosate was compared with representative GBHs, namely MON 52276 (European Union), MON 76473 (UK) and MON 76207 (USA), using the mammalian stem cell-based ToxTracker system. Here, MON 52276 and MON 76473, but not glyphosate and MON 76207, activated oxidative stress and deployed protein responses. Secondly, liver molecular profiling was performed in female Sprague-Dawley rats exposed to glyphosate or MON 52276 (at 0.5, 50 and 175 mg/kg bw/day glyphosate) for 90 days. MON 52276, but not glyphosate, increased hepatic steatosis and necrosis. MON 52276 and glyphosate altered gene expression in the liver, reflecting TP53 activation by DNA damage and regulation of circadian rhythm. The genes most affected in the liver were also altered in the kidneys. Small RNA profiling in the liver showed a decrease in miR-22 and miR-17 following MON 52276 ingestion. Glyphosate decreased miR-30, while miR-10 levels increased. Liver DNA methylation profiling revealed 5,727 and 4,496 differentially methylated CpG sites between control animals and animals exposed to glyphosate and MON 52,276, respectively. The formation of apurinic/apyrimidine DNA damage in the liver increased with glyphosate exposure. Overall, our results show that Roundup formulations induce more biological changes related to carcinogenesis than glyphosate.
2021
Use of Shotgun Metagenomics and Metabolomics to Evaluate the Impact of Glyphosate or Roundup MON 52276 on the Gut Microbiota and Serum Metabolome of Sprague-Dawley Rats. Robin MesnageMaxime Teixeira, Daniele Mandrioli, Laura Falcioni, Quinten Raymond Ducarmon, Romy Daniëlle Zwittink, Francesca Mazzacuva, Anna Caldwell, John Halket, Caroline Amiel, Jean-Michel Panoff, Fiorella Belpoggi, Michael Nicolas Antoniou. Environ Health Perspect. 2021. Doi : 10.1289/EHP6990.
Using metagenomics and metabolomics to assess the impact of glyphosate or Roundup MON 52276 on the gut microbiota and serum metabolome of Sprague-Dawley rats.
There is intense debate about whether glyphosate can inhibit the shikimate pathway of gastrointestinal microorganisms, with potential health implications.
We tested glyphosate and/or its herbicide formulation, Roundup MON 52276, to see how it affected the rat gut microbiome.
We combined metagenomics of the caecal microbiome with metabolomics of serum and cecum to assess the effects of glyphosate [0.5, 50, 175 mg/kg body weight (bw) per day or MON 52276 at the same glyphosate-equivalent doses, in a 90-day toxicity test in rats.
Results: Treatment with glyphosate and MON 52276 resulted in caeca accumulation of shikimic acid and 3-dehydroshikimic acid, suggesting inhibition of the 5-enolpyruvylshikimate-3-phosphate synthase of the shikimate pathway in the gut microbiome.
This study highlights the power of multi-omics approaches to study the toxic effects of pesticides. Multi-omics studies revealed that glyphosate and MON 52276 inhibited the shikimate pathway in the rat gut microbiome. Our results could be used to develop biomarkers for epidemiological studies to assess the effects of glyphosate herbicides on humans. https://doi.org/10.1289/EHP6990.
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.
2008
Factors to consider before production and commercialization of aquatic genetically modified organisms: the case of transgenic salmon. Olivier Le Curieux-Belfond, Louise Vandelac, Joseph Caron, Gilles-Éric Séralini. (2008). Environmental Science & Policy doi.org/10.1016/j.envsci.2008.10.001
Factors to consider before producing and marketing genetically modified aquatic organisms: the case of transgenic salmon
A transgenic fish on the market!
Numerous genetically modified plants have been developed, and four of them (soybean, maize, cotton and rapeseed), representing over 99% of commercial crops, are widely grown, mainly in the USA and America. However, all over the world, policy is still under development regarding the authorization of modified and/or cloned plants and animals for food or feed use, and their release into the environment. Commercial animal projects...
...the most advanced involve various species of fish, which are easier to transform genetically, notably because conception and development take place in water and with easy access to numerous eggs. An application for approval to market genetically modified (GM) salmon has been submitted to the US Food and Drug Administration (FDA). In the meantime, questions have been raised about the impacts of GM salmon, modified for productivity, on aquaculture, wildlife, ecosystems and human health. Here, we review these scientific studies and health, environmental, social and economic arguments. This article analyzes the current gaps in our knowledge of the impacts of transgenic fish, and proposes the legislative guidelines needed to protect the environment and human health, should the commercialization of animal genetically modified organisms (GMOs) be authorized.
2006
Horizontal genetic transfers. Jean-Michel Panoff , Christian Velot , Gilles-Éric Séralini (2006). Biofutur 269, September 2006.
When it comes to assessing the risks associated with the release of GMOs, horizontal transfers play a key role that should not be overlooked. Traditionally, biologists consider that transfers of genetic information within the living world are of two types: vertical transfers (VT) and horizontal transfers (HT).
TVs are essentially, on the one hand, sexuality in so-called "higher" organisms (including animals and plants), and on the other, scissiparity in a large proportion of microscopic organisms, including bacteria. Alongside TVs, THs correspond to the possibility, natural (N) or artificial (A), that an organism may capture a DNA fragment present in its immediate environment. According to the scientific literature, it is reasonable to consider that horizontal gene transfer is also a common mechanism by which biological organisms adapt to environmental stresses.
Possibility of detoxification :
2011
Defined plant extracts can protect human cells against combined xenobiotic effects. Céline Gasnier, Claire Laurant, Cécile Decroix-Laporte, Robin Mesnage, Emilie Clair, Carine Travert, Gilles-Eric Séralini. J Occup Med Toxicol. 2011 doi: 10.1186/1745-6673-6-3.
" Defined plant extracts can protect human cells from combined xenobiotic effects ".
Representative pollutants of common environmental contaminants induce intracellular toxicity in human cells, which is usually amplified in combination. We wanted to test common pathways of intoxication and detoxification in human embryonic and hepatic cell lines...
We used various pollutants such as Roundup residues, Bisphenol-A and Atrazine, as well as five specific herbal extracts called Circ1, Dig1, Dig2, Sp1 and Uro1 to understand whether or not specific molecular actions had taken place.
The kidneys and liver are major detoxification organs. We studied human embryonic kidney and liver cell lines E293 and HepG2. The intoxication was caused on the one hand by a formulation of one of the world's most widely used herbicides, Roundup 450 GT+ (glyphosate and specific adjuvants), and on the other by a mixture of Bisphenol-A and Atrazine, all present in surface waters. The preventive and curative effects of The preventive and curative effects of plant extracts were also measured on mitochondrial succinate dehydrogenase activity, on the entry of radiolabelled glyphosate (in Roundup) into cells, and on cytochromes P450 1A2 and 3A4 as well as glutathione-S-transferase.
Results: Clear pollutant toxicity was observed in both cell lines at very low sub-agricultural dilutions. Prevention of such phenomena occurred within 48 hours with the plant extracts tested, with success rates ranging from 25 to 34% for Roundup-intoxicated E293, and surprisingly up to 71% for HepG2. In contrast, after intoxication, no plant extract was able to restore E293 viability within 48 hours. However, two herbal combinations restored Bisphenol-A/Atrazine-intoxicated HepG2 up to 24-28%. Analysis of the underlying mechanisms revealed that the plant extracts were unable to prevent radiolabeled glyphosate from entering cells; however, Dig2 restored Roundup-disrupted CYP1A2 activity and had only a slight preventive effect on CYP3A4 and no effect on glutathione S-transferase.
In conclusion: environmental pollutants have intracellular effects that can be prevented, or partly cured, by specific herbal extracts in two human cell lines. This appears to be due at least in part to modulation of cytochromes P450.
2010
Dig1 protects against cell death provoked by glyphosate-based herbicides in human liver cell lines. Céline Gasnier, Nora Benachour, Emilie Clair, Carine Travert, Frédéric Langlois, Claire Laurant, Cécile Decroix-Laporte, Gilles-Eric Séralini. Jour. Occ. Med and Tox. 2010 doi : 10.1186/1745-6673-5-29.
" Dig1 protects against glyphosate herbicide-induced cell death in human liver cell lines ".
Pesticides used worldwide containing various adjuvants, such as Roundup formulations of glyphosate-based herbicides, can cause toxicity in vivo and in human cells. In order to understand their effects on liver cells, a major detoxification organ, we studied their mechanism of action and their possible protection by specific extracts of medicinal plants called Dig1...
The cytotoxicity pathways of four glyphosate herbicide formulations were investigated using human liver cell lines HepG2 and Hep3B, well-known models for studying the effects of xenobiotics. We monitored mitochondrial succinate dehydrogenase activity and caspases 3/7 for cell death and protection by Dig1, as well as cytochromes P450 1A1, 1A2, 3A4 and 2C9 and glutathione-S-transferase to address the mechanism of action.
All four Roundup formulations induce liver cell death, with adjuvants having more potent effects than glyphosate alone. Dig 1, which is non-cytotoxic and does not induce caspases on its own, is able to prevent Roundup-induced cell death in a time-dependent manner, with a significant efficacy of up to 89%, within 48 hrs. Furthermore, we demonstrated that it prevents caspase 3/7 activation and CYP3A4 enhancement, not GST reduction, but slightly inhibits CYP2C9 when added before Roundup.
In conclusion, Roundup is capable of inducing intracellular disruption in liver cell lines at various levels, but a mixture of Dig1 medicinal plant extracts can protect human cell lines to some extent against these pollutants. Together, the system provides a tool for studying intoxication and hepatic detoxification.