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Mesnage and Antoniou, 2020

Mesnage, Robin, & Antoniou, Michael N.; “Computational modelling provides insight into the effects of glyphosate on the shikimate pathway in the human gut microbiome;” Current Research in Toxicology, 2020, 1, 25-33; DOI: 10.1016/j.crtox.2020.04.001.

ABSTRACT:

The herbicide active ingredient glyphosate can affect the growth of microorganisms, which rely on the shikimate pathway for aromatic amino acid biosynthesis. However, it is uncertain whether glyphosate exposure could lead to perturbations in the population of human gut microbiota. We have addressed this knowledge gap by analysing publicly available datasets to provide new insights into possible effects of glyphosate on the human gut microbiome. Comparison of the abundance of the shikimate pathway in 734 paired metagenomes and metatranscriptomes indicated that most gut bacteria do not possess a complete shikimate pathway, and that this pathway is mostly transcriptionally inactive in the human gut microbiome. This suggests that gut bacteria are mostly aromatic amino acid auxotrophs and thus relatively resistant to a potential growth inhibition by glyphosate. As glyphosate blocking of the shikimate pathway is via inhibition of EPSPS, we classified E. coli EPSPS enzyme homologues as class I (sensitive to glyphosate) and class II (resistant to glyphosate). Among 44 subspecies reference genomes, accounting for 72% of the total assigned microbial abundance in 2144 human faecal metagenomes, 9 subspecies have class II EPSPS. The study of publicly available gut metagenomes also indicated that glyphosate might be degraded by some Proteobacteria in the human gut microbiome using the carbon–phosphorus lyase pathway. Overall, there is limited experimental evidence available for the effects of glyphosate on the human gut microbiome. Further investigations using more advanced molecular profiling techniques are needed to ascertain whether glyphosate and glyphosate-based herbicides can alter the function of the gut microbiome with consequent health implications. FULL TEXT


Mesnage, 2019

Mesnage, Robin, “Effects of dietary exposures to pesticide residues on the gut microbiome,” 2019, Presented 10/30/2019 at the London Microbiome Meeting 2019, Great Hall, King’s College London Strand Campus.

SUMMARY:

The gut microbiota: a major player in the toxicity of environmental pollutants?

FULL TEXT


Tsiaoussis et al., 2019

Tsiaoussis, J., Antoniou, M. N., Koliarakis, I., Mesnage, R., Vardavas, C. I., Izotov, B. N., Psaroulaki, A., & Tsatsakis, A.; “Effects of single and combined toxic exposures on the gut microbiome: Current knowledge and future directions;” Toxicology Letters, 2019, 312, 72-97; DOI: 10.1016/j.toxlet.2019.04.014.

ABSTRACT:

Human populations are chronically exposed to mixtures of toxic chemicals. Predicting the health effects of these mixtures require a large amount of information on the mode of action of their components. Xenobiotic metabolism by bacteria inhabiting the gastrointestinal tract has a major influence on human health. Our review aims to explore the literature for studies looking to characterize the different modes of action and outcomes of major chemical pollutants, and some components of cosmetics and food additives, on gut microbial communities in order to facilitate an estimation of their potential mixture effects. We identified good evidence that exposure to heavy metals, pesticides, nanoparticles, polycyclic aromatic hydrocarbons, dioxins, furans, polychlorinated biphenyls, and non-caloric artificial sweeteners affect the gut microbiome and which is associated with the development of metabolic, malignant, inflammatory, or immune diseases. Answering the question ‘Who is there?’ is not sufficient to define the mode of action of a toxicant in predictive modeling of mixture effects. Therefore, we recommend that new studies focus to simulate real-life exposure to diverse chemicals (toxicants, cosmetic/food additives), including as mixtures, and which combine metagenomics, metatranscriptomics and metabolomic analytical methods achieving in that way a comprehensive evaluation of effects on human health. FULL TEXT


Mesnage et al., 2019

Mesnage, R., Benbrook, C., & Antoniou, M. N.; “Insight into the confusion over surfactant co-formulants in glyphosate-based herbicides;” Food and Chemical Toxicology, 2019, 128, 137-145; DOI: 10.1016/j.fct.2019.03.053.

ABSTRACT:

Glyphosate is the active ingredient in glyphosate-based herbicides (GBHs). Other chemicals in GBHs are presumed as inert by regulatory authorities and are largely ignored in pesticide safety evaluations. We identified the surfactants in a cross-section of GBH formulations and compared their acute toxic effects. The first generation of polyethoxylated amine (POEA) surfactants (POE-tallowamine) in Roundup are markedly more toxic than glyphosate and heightened concerns of risks to human health, especially among heavily-exposed applicators. Beginning in the mid-1990s, first-generation POEAs were progressively replaced by other POEA surfactants, ethoxylated etheramines, which exhibited lower non-target toxic effects. Lingering concern over surfactant toxicity was mitigated at least in part within the European Union by the introduction of propoxylated quaternary ammonium surfactants. This class of POEA surfactants are approximately 100 times less toxic to aquatic ecosystems and human cells than previous GBH-POEA surfactants. As GBH composition is legally classified as confidential commercial information, confusion concerning the identity and concentrations of co-formulants is common and descriptions of test substances in published studies are often erroneous or incomplete. In order to resolve this confusion, laws requiring disclosure of the chemical composition of pesticide products could be enacted. Research to understand health implications from ingesting these substances is required. FULL TEXT


Mesnage et al., 2017

Mesnage, Robin, & Antoniou, Michael N, “Ignoring Adjuvant Toxicity Falsifies the Safety Profile of Commercial Pesticides,” Frontiers in Public Health, 2017, 5, 361. DOI: 10.3389/fpubh.2017.00361.

ABSTRACT:

Commercial formulations of pesticides are invariably not single ingredients. Instead they are cocktails of chemicals, composed of a designated pesticidal “active principle” and “other ingredients,” with the latter collectively also known as “adjuvants.” These include surfactants, antifoaming agents, dyes, etc. Some adjuvants are added to influence the absorption and stability of the active principle and thus promote its pesticidal action. Currently, the health risk assessment of pesticides in the European Union and in the United States focuses almost exclusively on the stated active principle. Nonetheless, adjuvants can also be toxic in their own right with numerous negative health effects having been reported in humans and on the environment. Despite the known toxicity of adjuvants, they are regulated differently from active principles, with their toxic effects being generally ignored. Adjuvants are not subject to an acceptable daily intake, and they are not included in the health risk assessment of dietary exposures to pesticide residues. Here, we illustrate this gap in risk assessment by reference to glyphosate, the most used pesticide active ingredient. We also investigate the case of neonicotinoid insecticides, which are strongly suspected to be involved in bee and bumblebee colony collapse disorder. Authors of studies sometimes use the name of the active principle (for example glyphosate) when they are testing a commercial formulation containing multiple (active principle plus adjuvant) ingredients. This results in confusion in the scientific literature and within regulatory circles and leads to a misrepresentation of the safety profile of commercial pesticides. Urgent action is needed to lift the veil on the presence of adjuvants in food and human bodily fluids, as well as in the environment (such as in air, water, and soil) and to characterize their toxicological properties. This must be accompanied by regulatory precautionary measures to protect the environment and general human population from some toxic adjuvants that are currently missing from risk assessments. FULL TEXT


Mesnage et al., 2016

Robin Mesnage, Sarah Z. Agapito-Tenfen, Vinicius Vilperte, George Renney, Malcolm Ward, Gilles-Eric Séralini, Rubens O. Nodari & Michael N. Antoniou, “An integrated multi-omics analysis of the NK603 Roundup-tolerant GM maize reveals metabolism  disturbances caused by the transformation process,” Nature: Scientific Reports, 2016, 6:37855, DOI: 10.1038/srep37855

ABSTRACT:

Glyphosate tolerant genetically modified (GM) maize NK603 was assessed as ‘substantially equivalent’ to its isogenic counterpart by a nutrient composition analysis in order to be granted market approval. We have applied contemporary in depth molecular profiling methods of NK603 maize kernels (sprayed or unsprayed with Roundup) and the isogenic corn to reassess its substantial equivalence status. Proteome profiles of the maize kernels revealed alterations in the levels of enzymes of glycolysis and TCA cycle pathways, which were reflective of an imbalance in energy metabolism. Changes in proteins and metabolites of glutathione metabolism were indicative of increased oxidative stress. The most pronounced metabolome differences between NK603 and its isogenic counterpart consisted of an increase in polyamines including N-acetyl-cadaverine (2.9-fold), N-acetylputrescine (1.8-fold), putrescine (2.7-fold) and cadaverine (28-fold), which depending on context can be either protective or a cause of toxicity. Our molecular profiling results show that NK603 and its isogenic control are not substantially equivalent. FULL TEXT


Séralini et al., 2014

Gilles-Eric Séralini, Emilie Clair, Robin Mesnage, Steeve Gress, Nicolas Defarge, Manuela Malatesta, Didier Hennequin and Joël Spiroux de Vendômois, “Republished study: long-term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize,” Environmental Sciences Europe, Bridging Science and Regulation at the Regional and European Level, 2014, 26:14. DOI: 10.1186/s12302-014-0014-5

ABSTRACT

BACKGROUND: The health effects of a Roundup-tolerant NK603 genetically modified (GM) maize(from 11% in the diet), cultivated with or without Roundup application and Roundup alone (from 0.1 ppb of the full pesticide containing glyphosate and adjuvants) in drinking water, were evaluated for 2 years in rats. This study constitutes a follow-up investigation of a 90-day feeding study conducted by Monsanto in order to obtain commercial release of this GMO, employing the same rat strain and analyzing biochemical parameters on the same number of animals per group as our investigation. Our research represents the first chronic study on these substances, in which all observations including tumors are reported chronologically. Thus, it was not designed as a carcinogenicity study. We report the major findings with 34 organs observed and 56 parameters analyzed at 11 time points for most organs.

RESULTS: Biochemical analyses confirmed very significant chronic kidney deficiencies, for all treatments and both sexes; 76% of the altered parameters were kidney-related.In treated males, liver congestions and necrosis were 2.5 to 5.5 times higher.Marked and severe nephropathies were also generally 1.3 to 2.3 times greater. In females, all treatment groups showed a two- to threefold increase in mortality,and deaths were earlier. This difference was also evident in three male groups fed with GM maize. All results were hormone- and sex-dependent, and the pathological profiles were comparable. Females developed large mammary tumors more frequently and before controls; the pituitary was the second most disabled organ; the sex hormonal balance was modified by consumption of GM maize and Roundup treatments.Males presented up to four times more large palpable tumors starting 600 days earlier than in the control group, in which only one tumor was noted. These results may be explained by not only the non-linear endocrine-disrupting effects of Roundup but also by the over expression of the EPSPS transgene or other mutational effects in the GM maize and their metabolic consequences.

CONCLUSION: Our findings imply that long-term (2 year) feeding trials need to be conducted to thoroughly evaluate the safety of GM foods and pesticides in their full commercial formulations.  FULL TEXT


Mesnage et al., 2015b

Robin Mesnage, Matthew Arno, Manuela Costanzo, Manuela Malatesta, Gilles-Eric Séralini and Michael N. Antoniou, “Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure,” Environmental Health, 2015, 14:70, DOI 10.1186/s12940-015-0056-1.

ABSTRACT:

BACKGROUND:  Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Converging evidence suggests that GBH, such as Roundup, pose a particular health risk to liver and kidneys although low environmentally relevant doses have not been examined. To address this issue, a 2-year study in rats administering 0.1 ppb Roundup (50 ng/L glyphosate equivalent) via drinking water (giving a daily intake of 4 ng/kg bw/day of glyphosate) was conducted. A marked increased incidence of anatomorphological and blood/urine biochemical changes was indicative of liver and kidney structure and functional pathology. In order to confirm these findings we have conducted a transcriptome microarray analysis of the liver and kidneys from these same animals.

RESULTS: The expression of 4224 and 4447 transcript clusters (a group of probes corresponding to a known or putative gene) were found to be altered respectively in liver and kidney (p < 0.01, q < 0.08). Changes in gene expression varied from −3.5 to 3.7 fold in liver and from −4.3 to 5.3 in kidneys. Among the 1319 transcript clusters whose expression was altered in both tissues, ontological enrichment in 3 functional categories among 868 genes were found. First, genes involved in mRNA splicing and small nucleolar RNA were mostly upregulated, suggesting disruption of normal spliceosome activity. Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption. Second, genes controlling chromatin structure (especially histone-lysine N-methyltransferases) were mostly upregulated. Third, genes related to respiratory chain complex I and the tricarboxylic acid cycle were mostly downregulated. Pathway analysis suggests a modulation of the mTOR and phosphatidylinositol signalling pathways. Gene disturbances associated with the chronic administration of ultra-low dose Roundup reflect a liver and kidney lipotoxic condition and increased cellular growth that may be linked with regeneration in response to toxic effects causing damage to tissues. Observed alterations in gene expression were consistent with fibrosis, necrosis, phospholipidosis, mitochondrial membrane dysfunction and ischemia, which correlate with and thus confirm observations of pathology made at an anatomical, histological and biochemical level.

CONCLUSION: Our results suggest that chronic exposure to a GBH in an established laboratory animal toxicity model system at an ultra-low, environmental dose can result in liver and kidney damage with potential significant health implications for animal and human populations.  FULL TEXT


Mesnage et al., 2015

R. Mesnage, N. Defarge, J. Spiroux de Vendomois, G.E. Seralini, “Potential toxic effects of glyphosate and its commercial formulations below regulatory limits,” Food and Chemical Toxicology, 2015, 84, DOI: 10.1016/J.FCT.2015.08.012.

ABSTRACT:

Glyphosate-based herbicides (GlyBH), including Roundup, are the most widely used pesticides worldwide. Their uses have increased exponentially since their introduction on the market. Residue levels in food or water, as well as human exposures, are escalating. We have reviewed the toxic effects of GlyBH measured below regulatory limits by evaluating the published literature and regulatory reports. We reveal a coherent body of evidence indicating that GlyBH could be toxic below the regulatory lowest observed adverse effect level for chronic toxic effects. It includes teratogenic, tumorigenic and hepatorenal effects. They could be explained by endocrine disruption and oxidative stress, causing metabolic alterations, depending on dose and exposure time. Some effects were detected in the range of the recommended acceptable daily intake. Toxic effects of commercial formulations can also be explained by GlyBH adjuvants, which have their own toxicity, but also enhance glyphosate toxicity. These challenge the assumption of safety of GlyBH at the levels at which they contaminate food and the environment, albeit these levels may fall below regulatory thresholds. Neurodevelopmental, reproductive, and transgenerational effects of GlyBH must be revisited, since a growing body of knowledge suggests the predominance of endocrine disrupting mechanisms caused by environmentally relevant levels of exposure. FULL TEXT

 


Benbrook, 2016c

John Peterson Myers, Michael N. Antoniou, Bruce Blumberg, Lynn Carroll, Theo Colborn, Lorne G. Everett, Michael Hansen, Philip J. Landrigan, Bruce P. Lanphear, Robin Mesnage, Laura N. Vandenberg, Frederick S. vom Saal, Wade V. Welshons and Charles M. Benbrook. “Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement,” Environmental Health, 2016, 15:19, DOI: 10.1186/s12940-016-0117-0.

ABSTRACT:

The broad-spectrum herbicide glyphosate (common trade name “Roundup”) was first sold to farmers in 1974. Since the late 1970s, the volume of glyphosate-based herbicides (GBHs) applied has increased approximately 100-fold. Further increases in the volume applied are likely due to more and higher rates of application in response to the widespread emergence of glyphosate-resistant weeds and new, pre-harvest, dessicant use patterns. GBHs were developed to replace or reduce reliance on herbicides causing well-documented problems associated with drift and crop damage, slipping efficacy, and human health risks. Initial industry toxicity testing suggested that GBHs posed relatively low risks to non-target species, including mammals, leading regulatory authorities worldwide to set high acceptable exposure limits. To accommodate changes in GBH use patterns associated with genetically engineered, herbicide-tolerant crops, regulators have dramatically increased tolerance levels in maize, oilseed (soybeans and canola), and alfalfa crops and related livestock feeds. Animal and epidemiology studies published in the last decade, however, point to the need for a fresh look at glyphosate toxicity. Furthermore, the World Health Organization’s International Agency for Research on Cancer recently concluded that glyphosate is “probably carcinogenic to humans.” In response to changing GBH use patterns and advances in scientific understanding of their potential hazards, we have produced a Statement of Concern drawing on emerging science relevant to the safety of GBHs. Our Statement of Concern considers current published literature describing GBH uses, mechanisms of action, toxicity in laboratory animals, and epidemiological studies. It also examines the derivation of current human safety standards. We conclude that: (1) GBHs are the most heavily applied herbicide in the world and usage continues to rise; (2) Worldwide, GBHs often contaminate drinking water sources, precipitation, and air, especially in agricultural regions; (3) The half-life of glyphosate in water and soil is longer than previously recognized; (4) Glyphosate and its metabolites are widely present in the global soybean supply; (5) Human exposures to GBHs are rising; (6) Glyphosate is now authoritatively classified as a probable human carcinogen; (7) Regulatory estimates of tolerable daily intakes for glyphosate in the United States and European Union are based on outdated science. We offer a series of recommendations related to the need for new investments in epidemiological studies, biomonitoring, and toxicology studies that draw on the principles of endocrinology to determine whether the effects of GBHs are due to endocrine disrupting activities. We suggest that common commercial formulations of GBHs should be prioritized for inclusion in government-led toxicology testing programs such as the U.S. National Toxicology Program, as well as for biomonitoring as conducted by the U.S. Centers for Disease Control and Prevention.  FULL TEXT