Publications by authors named "Robin Mesnage"

55 Publications

Commentary: Novel strategies and new tools to curtail the health effects of pesticides.

Environ Health 2021 Aug 3;20(1):87. Epub 2021 Aug 3.

Gene Expression and Therapy Group, Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, Guy's Hospital, London, UK.

Background: Flaws in the science supporting pesticide risk assessment and regulation stand in the way of progress in mitigating the human health impacts of pesticides. Critical problems include the scope of regulatory testing protocols, the near-total focus on pure active ingredients rather than formulated products, lack of publicly accessible information on co-formulants, excessive reliance on industry-supported studies coupled with reticence to incorporate published results in the risk assessment process, and failure to take advantage of new scientific opportunities and advances, e.g. biomonitoring and "omics" technologies.

Recommended Actions: Problems in pesticide risk assessment are identified and linked to study design, data, and methodological shortcomings. Steps and strategies are presented that have potential to deepen scientific knowledge of pesticide toxicity, exposures, and risks. We propose four solutions: (1) End near-sole reliance in regulatory decision-making on industry-supported studies by supporting and relying more heavily on independent science, especially for core toxicology studies. The cost of conducting core toxicology studies at labs not affiliated with or funded directly by pesticide registrants should be covered via fees paid by manufacturers to public agencies. (2) Regulators should place more weight on mechanistic data and low-dose studies within the range of contemporary exposures. (3) Regulators, public health agencies, and funders should increase the share of exposure-assessment resources that produce direct measures of concentrations in bodily fluids and tissues. Human biomonitoring is vital in order to quickly identify rising exposures among vulnerable populations including applicators, pregnant women, and children. (4) Scientific tools across disciplines can accelerate progress in risk assessments if integrated more effectively. New genetic and metabolomic markers of adverse health impacts and heritable epigenetic impacts are emerging and should be included more routinely in risk assessment to effectively prevent disease.

Conclusions: Preventing adverse public health outcomes triggered or made worse by exposure to pesticides will require changes in policy and risk assessment procedures, more science free of industry influence, and innovative strategies that blend traditional methods with new tools and mechanistic insights.
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http://dx.doi.org/10.1186/s12940-021-00773-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330079PMC
August 2021

Redox Biomarker Baseline Levels in Cattle Tissues and Their Relationships with Meat Quality.

Antioxidants (Basel) 2021 Jun 15;10(6). Epub 2021 Jun 15.

Department of Biochemistry and Biotechnology, University of Thessaly, Viopolis, Mezourlo, 41500 Larissa, Greece.

Cattle breeds or crossbreds with high productivity traits have been developed to meet a growing demand for food. When intensive farming practices are followed, animals face several challenges which can result in poor performance, compromised welfare and the reduced quality of their products. Our study aims to highlight the resting values of the physiological oxidative stress that three cattle breeds exhibit, and their potential relationship with meat quality. For this purpose, we determined the levels of five common redox biomarkers (glutathione (GSH), catalase (CAT), total antioxidant capacity (TAC), thiobarbituric reactive substances (TBARS) and protein carbonyls (CARBS)) in the tissues of three commonly used beef cattle breeds (Charolais (CHA), Limousin (LIM) and Simmental (SIM)) and their association with specific meat quality traits that depend on color, pH and texture. The results revealed that LIM cattle breed animals have elevated intrinsic antioxidant defense systems in comparison to CHA and SIM cattle breed animals. In addition, the meat quality parameters were associated with the redox biomarkers. We propose that the determination of specific antioxidant parameters in the blood might be used as potential biomarkers to predict meat quality. This would allow farmers to nutritionally intervene to improve the quality of their products.
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http://dx.doi.org/10.3390/antiox10060958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232099PMC
June 2021

Long-term fasting improves lipoprotein-associated atherogenic risk in humans.

Eur J Nutr 2021 Oct 7;60(7):4031-4044. Epub 2021 May 7.

Buchinger Wilhelmi Clinic, Wilhelm-Beck-Straße 27, 88662, Überlingen, Germany.

Purpose: Dyslipidemia is a major health concern associated with an increased risk of cardiovascular mortality. Long-term fasting (LF) has been shown to improve plasma lipid profile. We performed an in-depth investigation of lipoprotein composition.

Methods: This observational study included 40 volunteers (50% men, aged 32-65 years), who underwent a medically supervised fast of 14 days (250 kcal/day). Changes in lipid and lipoprotein levels, as well as in lipoprotein subclasses and particles, were measured by ultracentrifugation and nuclear magnetic resonance (NMR) at baseline, and after 7 and 14 fasting days.

Results: The largest changes were found after 14 fasting days. There were significant reductions in triglycerides (TG, - 0.35 ± 0.1 mmol/L), very low-density lipoprotein (VLDL)-TG (- 0.46 ± 0.08 mmol/L), VLDL-cholesterol (VLDL-C, - 0.16 ± 0.03 mmol/L) and low-density lipoprotein (LDL)-C (- 0.72 ± 0.14 mmol/L). Analysis of LDL subclasses showed a significant decrease in LDL1-C (- 0.16 ± 0.05 mmol/L), LDL2-C (- 0.30 ± 0.06 mmol/L) and LDL3-C (- 0.27 ± 0.05 mmol/L). NMR spectroscopy showed a significant reduction in large VLDL particles (- 5.18 ± 1.26 nmol/L), as well as large (- 244.13 ± 39.45 nmol/L) and small LDL particles (- 38.45 ± 44.04 nmol/L). A significant decrease in high-density lipoprotein (HDL)-C (- 0.16 ± 0.04 mmol/L) was observed. By contrast, the concentration in large HDL particles was significantly raised. Apolipoprotein A1 decreased significantly whereas apolipoprotein B, lipoprotein(a), fibrinogen and high-sensitivity C-reactive protein were unchanged.

Conclusion: Our results suggest that LF improves lipoprotein levels and lipoprotein subclasses and ameliorates the lipoprotein-associated atherogenic risk profile, suggesting a reduction in the cardiovascular risk linked to dyslipidemia.

Trial Registration: Study registration number: DRKS-ID: DRKS00010111 Date of registration: 03/06/2016 "retrospectively registered".
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http://dx.doi.org/10.1007/s00394-021-02578-0DOI Listing
October 2021

Impacts of a glyphosate-based herbicide on the gut microbiome of three earthworm species ( and ): A pilot study.

Toxicol Rep 2021 31;8:753-758. Epub 2021 Mar 31.

Department of Medical and Molecular Genetics, Kings College London, United Kingdom.

While the impact of glyphosate-based herbicides (GBHs) on earthworms has been studied, little is known about their effects on the earthworm gut microbiome. This study investigated the impact of a GBH on the gut microbial communities of three earthworm species ( and ). Earthworm species accommodated in soil were sprayed with 115.49 mL/m² of Roundup® Alphée or water. Gut microbiome composition was analysed using 16S rRNA Bacterial Tag-Encoded FLX Amplicon Pyrosequencing (bTEFAP) at the 8th week post-herbicide application. A profound shift in bacterial populationswas observed in all exposed earthworms with becoming the dominant phylum. Affected bacteria were mostly from the genus , and , which together represented approximately 80 % of the total abundance assigned at the genus level in exposed earthworms, while they were present at a minor abundance (∼1%) in unexposed earthworms. Although consistent results were observed between the three groups of worm species, it is not possible to generalize these outcomes due to a lack of biological replicates, which does not allow for inferential statistical analysis. Nevertheless, our study is the first to report the effects of a GBH on the earthworm gut microbiome and paves the way for future more comprehensive investigations.
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http://dx.doi.org/10.1016/j.toxrep.2021.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027525PMC
March 2021

Multi-omics phenotyping of the gut-liver axis reveals metabolic perturbations from a low-dose pesticide mixture in rats.

Commun Biol 2021 04 14;4(1):471. Epub 2021 Apr 14.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, London, UK.

Health effects of pesticides are not always accurately detected using the current battery of regulatory toxicity tests. We compared standard histopathology and serum biochemistry measures and multi-omics analyses in a subchronic toxicity test of a mixture of six pesticides frequently detected in foodstuffs (azoxystrobin, boscalid, chlorpyrifos, glyphosate, imidacloprid and thiabendazole) in Sprague-Dawley rats. Analysis of water and feed consumption, body weight, histopathology and serum biochemistry showed little effect. Contrastingly, serum and caecum metabolomics revealed that nicotinamide and tryptophan metabolism were affected, which suggested activation of an oxidative stress response. This was not reflected by gut microbial community composition changes evaluated by shotgun metagenomics. Transcriptomics of the liver showed that 257 genes had their expression changed. Gene functions affected included the regulation of response to steroid hormones and the activation of stress response pathways. Genome-wide DNA methylation analysis of the same liver samples showed that 4,255 CpG sites were differentially methylated. Overall, we demonstrated that in-depth molecular profiling in laboratory animals exposed to low concentrations of pesticides allows the detection of metabolic perturbations that would remain undetected by standard regulatory biochemical measures and which could thus improve the predictability of health risks from exposure to chemical pollutants.
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http://dx.doi.org/10.1038/s42003-021-01990-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046807PMC
April 2021

Urinary excretion of herbicide co-formulants after oral exposure to roundup MON 52276 in rats.

Environ Res 2021 06 1;197:111103. Epub 2021 Apr 1.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, London, SE1 9RT, UK. Electronic address:

The toxicity of surfactants, which are an integral component of glyphosate-formulated products is an underexplored and highly debated subject. Since biomonitoring human exposure to glyphosate co-formulants is considered as a public health priority, we developed and validated a high-resolution mass spectrometry method to measure the urinary excretion of surfactants present in Roundup MON 52276, the European Union (EU) representative formulation of glyphosate-based herbicides. Quantification was performed measuring the 5 most abundant compounds in the mixture. We validated the method and showed that it is highly accurate, precise and reproducible with a limit of detection of 0.0004 μg/mL. We used this method to estimate the oral absorption of MON 52276 surfactants in Sprague-Dawley rats exposed to three concentrations of MON 52276 via drinking water for 90 days. MON 52276 surfactants were readily detected in urine of rats administered with this commercial Roundup formulation starting from a low concentration corresponding to the EU glyphosate acceptable daily intake. Our results provide a first step towards the implementation of surfactant co-formulant biomonitoring in human populations.
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http://dx.doi.org/10.1016/j.envres.2021.111103DOI Listing
June 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.

Environ Health Perspect 2021 Jan 27;129(1):17005. Epub 2021 Jan 27.

Gene Expression and Therapy Group, Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences & Medicine, Guy's Hospital, London, UK.

Background: There is intense debate on whether glyphosate can inhibit the shikimate pathway of gastrointestinal microorganisms, with potential health implications.

Objectives: We tested whether glyphosate or its representative EU herbicide formulation Roundup MON 52276 affects the rat gut microbiome.

Methods: We combined cecal microbiome shotgun metagenomics with serum and cecum metabolomics to assess the effects of glyphosate [0.5, 50, ] or MON 52276 at the same glyphosate-equivalent doses, in a 90-d toxicity test in rats.

Results: Glyphosate and MON 52276 treatment resulted in ceca accumulation of shikimic acid and 3-dehydroshikimic acid, suggesting inhibition of 5-enolpyruvylshikimate-3-phosphate synthase of the shikimate pathway in the gut microbiome. Cysteinylglycine, , and valylglycine levels were elevated in the cecal microbiome following glyphosate and MON 52276 treatments. Altered cecum metabolites were not differentially expressed in serum, suggesting that the glyphosate and MON 52276 impact on gut microbial metabolism had limited consequences on physiological biochemistry. Serum metabolites differentially expressed with glyphosate treatment were associated with nicotinamide, branched-chain amino acid, methionine, cysteine, and taurine metabolism, indicative of a response to oxidative stress. MON 52276 had similar, but more pronounced, effects than glyphosate on the serum metabolome. Shotgun metagenomics of the cecum showed that treatment with glyphosate and MON 52276 resulted in higher levels of spp., , , and . was higher only with MON 52276 exposure. culture assays with strains showed that Roundup GT plus inhibited growth at concentrations at which MON 52276 and glyphosate had no effect.

Discussion: Our study highlights the power of multi-omics approaches to investigate the toxic effects of pesticides. Multi-omics revealed that glyphosate and MON 52276 inhibited the shikimate pathway in the rat gut microbiome. Our findings could be used to develop biomarkers for epidemiological studies aimed at evaluating the effects of glyphosate herbicides on humans. https://doi.org/10.1289/EHP6990.
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http://dx.doi.org/10.1289/EHP6990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839352PMC
January 2021

Blood Pressure Changes in 1610 Subjects With and Without Antihypertensive Medication During Long-Term Fasting.

J Am Heart Assoc 2020 12 23;9(23):e018649. Epub 2020 Nov 23.

Buchinger Wilhelmi Clinic Überlingen Germany.

Background We investigated daily blood pressure (BP) changes during fasting periods ranging from 4 to 41 (10.0±3.8) days in a cohort of 1610 subjects, including 920 normotensive, 313 hypertensive nonmedicated, and 377 hypertensive medicated individuals. Methods and Results Subjects underwent a multidisciplinary fasting program with a daily intake of ≈250 kcal. Weight and stress scores decreased during fasting, and the well-being index increased, documenting a good tolerability. BP mean values decreased from 126.2±18.6/81.4±11.0 to 119.7±15.9/77.6±9.8 mm Hg (mean change, -6.5/3.8 mm Hg). BP changes were larger for hypertensive nonmedicated subjects (>140/90 mm Hg) and reduced by 16.7/8.8 mm Hg. This reduction reached 24.7/13.1 mm Hg for hypertensive nonmedicated subjects (n=76) with the highest BP (>160/100 mm Hg). In the normotensive group, BP decreased moderately by 3.0/1.9 mm Hg. Interestingly, we documented an increase of 6.3/2.2 mm Hg in a subgroup of 69 female subjects with BP <100/60 mm Hg. In the hypertensive medicated group, although BP decreased from 134.6/86.0 to 127.3/81.3 mm Hg, medication was stopped in 23.6% of the subjects, whereas dosage was reduced in 43.5% and remained unchanged in 19.4%. The decrease in BP was larger in subjects fasting longer. Baseline metabolic parameters, such as body mass index and glucose levels, as well as age, can be used to predict the amplitude of the BP decrease during fasting with a machine learning model. Conclusions Long-term fasting tends to decrease BP in subjects with elevated BP values. This effect persisted during the 4 days of stepwise food reintroduction, even when subjects stopped their antihypertensive medication. Registration URL: https://www.drks.de/drks_web/; Unique identifier: DRKS00010111.
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http://dx.doi.org/10.1161/JAHA.120.018649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763762PMC
December 2020

Interplay between oxidative damage, the redox status, and metabolic biomarkers during long-term fasting.

Food Chem Toxicol 2020 Nov 25;145:111701. Epub 2020 Aug 25.

Buchinger Wilhelmi Clinic, 88662, Überlingen, Germany. Electronic address:

Obesity and its related metabolic disorders, as well as infectious diseases like covid-19, are important health risks nowadays. It was recently documented that long-term fasting improves metabolic health and enhanced the total antioxidant capacity. The present study investigated the influence of a 10-day fasting on markers of the redox status in 109 subjects. Reducing power, 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical cation(ABTS) radical scavenging capacity, and hydroxyl radical scavenging capacity increased significantly, and indicated an increase of circulating antioxidant levels. No differences were detected in superoxide scavenging capacity, protein carbonyls, and superoxide dismutase when measured at baseline and after 10 days of fasting. These findings were concomitant to a decrease in blood glucose, insulin, glycated hemoglobin (HbA1c), total cholesterol, low-density lipoprotein (LDL) and triglycerides as well as an increase in total cholesterol/high-density lipoprotein (HDL) ratio. In addition, the well-being index as well as the subjective energy levels increased, documenting a good tolerability. There was an interplay between redox and metabolic parameters since lipid peroxidation baseline levels (thiobarbituric acid reactive substances [TBARS]) affected the ability of long-term fasting to normalize lipid levels. A machine learning model showed that a combination of antioxidant parameters measured at baseline predicted the efficiency of the fasting regimen to decrease LDL levels. In conclusion, it was demonstrated that long-term fasting enhanced the endogenous production of antioxidant molecules, that act protectively against free radicals, and in parallel improved the metabolic health status. Our results suggest that the outcome of long-term fasting strategies could be depending on the baseline values of the antioxidative and metabolic status of subjects.
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http://dx.doi.org/10.1016/j.fct.2020.111701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446623PMC
November 2020

Chronic Inflammation in the Context of Everyday Life: Dietary Changes as Mitigating Factors.

Int J Environ Res Public Health 2020 06 10;17(11). Epub 2020 Jun 10.

Department Forensic Sciences and Toxicology, University of Crete, Faculty of Medicine, 71003 Heraklion, Greece.

The lifestyle adopted by most people in Western societies has an important impact on the propensity to metabolic disorders (e.g., diabetes, cancer, cardiovascular disease, neurodegenerative diseases). This is often accompanied by chronic low-grade inflammation, driven by the activation of various molecular pathways such as STAT3 (signal transducer and activator of transcription 3), IKK (IκB kinase), MMP9 (matrix metallopeptidase 9), MAPK (mitogen-activated protein kinases), COX2 (cyclooxigenase 2), and NF-Kβ (nuclear factor kappa-light-chain-enhancer of activated B cells). Multiple intervention studies have demonstrated that lifestyle changes can lead to reduced inflammation and improved health. This can be linked to the concept of real-life risk simulation, since humans are continuously exposed to dietary factors in small doses and complex combinations (e.g., polyphenols, fibers, polyunsaturated fatty acids, etc.). Inflammation biomarkers improve in patients who consume a certain amount of fiber per day; some even losing weight. Fasting in combination with calorie restriction modulates molecular mechanisms such as m-TOR, FOXO, NRF2, AMPK, and sirtuins, ultimately leads to significantly reduced inflammatory marker levels, as well as improved metabolic markers. Moving toward healthier dietary habits at the individual level and in publicly-funded institutions, such as schools or hospitals, could help improving public health, reducing healthcare costs and improving community resilience to epidemics (such as COVID-19), which predominantly affects individuals with metabolic diseases.
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http://dx.doi.org/10.3390/ijerph17114135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312944PMC
June 2020

Influence of Long-Term Fasting on Blood Redox Status in Humans.

Antioxidants (Basel) 2020 Jun 6;9(6). Epub 2020 Jun 6.

Department of Biochemistry-Biotechnology, School of Health Sciences, University of Thessaly, Viopolis, 41500 Larissa, Greece.

Fasting is increasingly practiced to improve health and general well-being, as well as for its cytoprotective effects. Changes in blood redox status, linked to the development of a variety of metabolic diseases, have been recently documented during calorie restriction and intermittent fasting, but not with long-term fasting (LF). We investigated some parameters of the blood redox profile in 109 subjects before and after a 10-day fasting period. Fasting resulted in a significant reduction in body weight, improved well-being and had a beneficial modulating effect on blood lipids and glucose regulation. We observed that fasting decreased lipid peroxidation (TBARS) and increased total antioxidant capacity (TAC) in plasma, concomitant with a uric acid elevation, known to be associated with fasting and did not cause gout attacks. Reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx) and catalase in erythrocytes did not show significant changes. In addition, reduction in body weight, waist circumference, and glucose levels were associated to a reduced lipid peroxidation. Similar results were obtained by grouping subjects on the basis of the changes in their GSH levels, showing that a period of 10 days fasting improves blood redox status regardless of GSH status in the blood.
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http://dx.doi.org/10.3390/antiox9060496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346198PMC
June 2020

Overview of the effects of chemical mixtures with endocrine disrupting activity in the context of real-life risk simulation: An integrative approach (Review).

World Acad Sci J 2019 Jul 5;1(4):157-164. Epub 2019 Aug 5.

Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71409 Heraklion.

Research over the past years has indicated that chronic human exposure to very low doses of various chemical species in mixtures and administered via different routes (percutaneous, orally, etc.) should be the main focus of new biochemical and toxicological studies. Humans have daily contact with various chemicals, such as food additives, pesticides from fruits/vegetables, antibiotics (and other veterinary drugs) from meat, different types of preservatives from cosmetics, to name a few. Simultaneous exposure to this wide array of chemicals does not produce immediate effects, but summative effect/s over time that may be clinically manifested several years thereafter. Classical animal studies designed to test the toxic outcome of a single chemical are not suitable to assess, and then extrapolate to humans, the effects of a whole mixture of chemicals. Testing the aftermath of a combination of chemicals, at low doses, around or below the no observed adverse effect is stressed by many toxicologists. Thus, there is a need to reformulate the design of biochemical and toxicological studies in order to perform real-life risk simulation. This review discuss the potential use of computational methods as a complementary tool for and toxicity tests with a high predictive potential that could contribute to reduce animal testing, cost and time, when assessing the effects of chemical combinations. This review focused on the use of these methods to predict the potential endocrine disrupting activity of a mixture of chemicals.
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http://dx.doi.org/10.3892/wasj.2019.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188405PMC
July 2019

Computational modelling provides insight into the effects of glyphosate on the shikimate pathway in the human gut microbiome.

Curr Res Toxicol 2020 Jun 22;1:25-33. Epub 2020 Apr 22.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, 8th Floor, Tower Wing, Great Maze Pond, London SE1 9RT, United Kingdom.

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 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.
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http://dx.doi.org/10.1016/j.crtox.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320642PMC
June 2020

Transcriptome profiling of the fungus Aspergillus nidulans exposed to a commercial glyphosate-based herbicide under conditions of apparent herbicide tolerance.

Environ Res 2020 03 7;182:109116. Epub 2020 Jan 7.

CRIIGEN, 42 Rue de Lisbonne, 75008, Paris, France; Equipe VEAC, Université Paris-Sud, Faculté des Sciences, Bât. 350, Avenue Jean Perrin, 91405, Orsay, France; Pôle Risques MRSH-CNRS, EA2608, Université de Caen, Esplanade de la Paix, 14032, Caen, France. Electronic address:

Glyphosate-based herbicides, such as Roundup®, are the most widely used non-selective, broad-spectrum herbicides. The release of these compounds in large amounts into the environment is susceptible to affect soil quality and health, especially because of the non-target effects on a large range of organisms including soil microorganisms. The soil filamentous fungus Aspergillus nidulans, a well-characterized experimental model organism that can be used as a bio-indicator for agricultural soil health, has been previously shown to be highly affected by Roundup GT Plus (R450: 450 g/L of glyphosate) at concentrations far below recommended agricultural application rate, including at a dose that does not cause any macroscopic effect. In this study, we determined alterations in the transcriptome of A. nidulans when exposed to R450 at a dose corresponding to the no-observed-adverse-effect level (NOAEL) for macroscopic parameters. A total of 1816 distinct genes had their expression altered. The most affected biological functions were protein synthesis, amino acids and secondary metabolisms, stress response, as well as detoxification pathways through cytochromes P450, glutathione-S-transferases, and ABC transporters. These results partly explain the molecular mechanisms underlying alterations in growth parameters detected at higher concentrations for this ascomycete fungus. In conclusion, our results highlight molecular disturbances in a soil fungus under conditions of apparent tolerance to the herbicide, and thus confirm the need to question the principle of "substantial equivalence" when applied to plants made tolerant to herbicides.
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http://dx.doi.org/10.1016/j.envres.2020.109116DOI Listing
March 2020

Changes in human gut microbiota composition are linked to the energy metabolic switch during 10 d of Buchinger fasting.

J Nutr Sci 2019 12;8:e36. Epub 2019 Nov 12.

Buchinger Wilhelmi Clinic, Wilhelm-Beck-Straße 27, 88662 Überlingen, Germany.

Fasting is increasingly popular to manage metabolic and inflammatory diseases. Despite the role that the human gut microbiota plays in health and diseases, little is known about its composition and functional capacity during prolonged fasting when the external nutrient supply is reduced or suppressed. We analysed the effects of a 10-d periodic fasting on the faecal microbiota of fifteen healthy men. Participants fasted according to the peer-reviewed Buchinger fasting guidelines, which involve a daily energy intake of about 1046 kJ (250 kcal) and an enema every 2 d. Serum biochemistry confirmed the metabolic switch from carbohydrates to fatty acids and ketones. Emotional and physical well-being were enhanced. Faecal 16S rRNA gene amplicon sequencing showed that fasting caused a decrease in the abundance of bacteria known to degrade dietary polysaccharides such as Lachnospiraceae and Ruminococcaceae. There was a concomitant increase in Bacteroidetes and Proteobacteria ( and ), known to use host-derived energy substrates. Changes in taxa abundance were associated with serum glucose and faecal branched-chain amino acids (BCAA), suggesting that fasting-induced changes in the gut microbiota are associated with host energy metabolism. These effects were reversed after 3 months. SCFA levels were unchanged at the end of the fasting. We also monitored intestinal permeability and inflammatory status. IL-6, IL-10, interferon γ and TNFα levels increased when food was reintroduced, suggesting a reactivation of the postprandial immune response. We suggest that changes in the gut microbiota are part of the physiological adaptations to a 10-d periodic fasting, potentially influencing its beneficial health effects.
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http://dx.doi.org/10.1017/jns.2019.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861737PMC
July 2020

Glyphosate does not substitute for glycine in proteins of actively dividing mammalian cells.

BMC Res Notes 2019 Aug 8;12(1):494. Epub 2019 Aug 8.

DC Biosciences, James Lindsay Place, Dundee, DD1 5JJ, UK.

Objectives: Glyphosate (N-phosphonomethyl glycine) and its commercial herbicide formulations have been shown to exert toxicity via various mechanisms. It has been asserted that glyphosate substitutes for glycine in polypeptide chains leading to protein misfolding and toxicity. However, as no direct evidence exists for glycine to glyphosate substitution in proteins, including in mammalian organisms, we tested this claim by conducting a proteomics analysis of MDA-MB-231 human breast cancer cells grown in the presence of 100 mg/L glyphosate for 6 days. Protein extracts from three treated and three untreated cell cultures were analysed as one TMT-6plex labelled sample, to highlight a specific pattern (+/+/+/-/-/-) of reporter intensities for peptides bearing true glyphosate treatment induced-post translational modifications as well as allowing an investigation of the total proteome.

Results: Comparative statistical analysis of global proteome changes between glyphosate treated and non-treated samples did not show significant differences. Crucially, filtering of data to focus analysis on peptides potentially bearing glycine for glyphosate replacement revealed that the TMT reporter intensity pattern of all candidates showed conclusively that they are all false discoveries, with none displaying the expected TMT pattern for such a substitution. Thus, the assertion that glyphosate substitutes for glycine in protein polypeptide chains is incorrect.
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http://dx.doi.org/10.1186/s13104-019-4534-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686468PMC
August 2019

Relationship between faecal microbiota and plasma metabolome in rats fed NK603 and MON810 GM maize from the GMO90+ study.

Food Chem Toxicol 2019 Sep 3;131:110547. Epub 2019 Jun 3.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom. Electronic address:

Safety concerns arising from the consumption of foods derived from genetically modified (GM) crops remains a controversial subject. We report here a faecal microbiota compositional analysis in Wistar rats from the GMO90 + study, which fed glyphosate-tolerant NK603 (+/- Roundup application) and Bt toxin MON810 GM maize for 6 months in comparison to their closest non-GM isogenic lines. We first integrated the faecal microbiota compositional data with results from plasma metabolomics to understand which bacterial species can influence host metabolism. Coriobacteriaceae and Acetatifactor significantly predicted plasma metabolic profile in males, while Bifidobacterium and Ruminococcus were able to predict female plasma metabolites. We then investigated the differences in fecal microbiota composition between group of rats fed MON810 or NK603 GM maize in comparison to their isogenic lines. Bacterial community richness was not altered by the test diets. There were no statistically significant differences in taxa abundance in the rat faecal microbiota that we could attribute to the consumption of either MON810 or NK603. We show that the consumption of the widely cultivated GM maize varieties NK603 and MON810 even up to 33% of the total diet had no effect on the status of the faecal microbiota compared to non-GM near isogenic lines.
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http://dx.doi.org/10.1016/j.fct.2019.05.055DOI Listing
September 2019

Quizalofop-p-Ethyl Induces Adipogenesis in 3T3-L1 Adipocytes.

Toxicol Sci 2019 08;170(2):452-461

Department of Medical and Molecular Genetics, School of Basic and Biomedical Sciences, Faculty of Life Sciences & Medicine, Gene Expression and Therapy Group, King's College London, Guy's Hospital, London SE1 9RT, UK.

Exposure to endocrine disrupting chemicals is an established risk factor for obesity. The most commonly used pesticide active ingredients have never been tested in an adipogenesis assay. We tested for the first time the potential of glyphosate, 2, 4-dichlorophenoxyacetic acid, dicamba, mesotrione, isoxaflutole, and quizalofop-p-ethyl (QpE) to induce lipid accumulation in murine 3T3-L1 adipocytes. Only QpE caused a dose-dependent statistically significant triglyceride accumulation from a concentration of 5 up to 100 µM. The QpE commercial formulation Targa Super was 100 times more cytotoxic than QpE alone. Neither the estrogen receptor antagonist ICI 182, 780 nor the glucocorticoid receptor antagonist RU486 was able to block the QpE-induced lipid accumulation. RNAseq analysis of 3T3-L1 adipocytes exposed to QpE suggests that this compound exerts its lipid accumulation effects via a peroxisome proliferator-activated receptor gamma (PPARγ)-mediated pathway, a nuclear receptor whose modulation influences lipid metabolism. QpE was further shown to be active in a PPARγ reporter gene assay at 100 µM, reaching 4% of the maximal response produced by rosiglitazone, which acts as a positive control. This indicates that lipid accumulation induced by QpE is only in part caused by PPARγ activation. The lipid accumulation capability of QpE we observe suggest that this pesticide, whose use is likely to increase in coming years may have a hitherto unsuspected obesogenic property.
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http://dx.doi.org/10.1093/toxsci/kfz097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657571PMC
August 2019

Effects of single and combined toxic exposures on the gut microbiome: Current knowledge and future directions.

Toxicol Lett 2019 Sep 27;312:72-97. Epub 2019 Apr 27.

Laboratory of Toxicology, Medical School, University of Crete, Voutes, 71409 Heraklion, Crete, Greece; Department of Analytical, Toxicology, Pharmaceutical Chemistry and Pharmacognosy, Sechenov University, 119991 Moscow, Russia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.toxlet.2019.04.014DOI Listing
September 2019

Insight into the confusion over surfactant co-formulants in glyphosate-based herbicides.

Food Chem Toxicol 2019 Jun 3;128:137-145. Epub 2019 Apr 3.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.

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 ∼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.
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http://dx.doi.org/10.1016/j.fct.2019.03.053DOI Listing
June 2019

Author Correction: An integrated multi-omics analysis of the NK603 Roundup-tolerant GM maize reveals metabolism disturbances caused by the transformation process.

Sci Rep 2019 Mar 15;9(1):4727. Epub 2019 Mar 15.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.

A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-39021-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420507PMC
March 2019

Addressing concerns over the fate of DNA derived from genetically modified food in the human body: A review.

Food Chem Toxicol 2019 Feb 21;124:423-430. Epub 2018 Dec 21.

Department of Biotechnology, Chonnam National University, Yeosu, Chonnam, 59626, Republic of Korea. Electronic address:

Global commercialization of GM food and feed has stimulated much debate over the fate of GM food-derived DNA in the body of the consumer and as to whether it poses any health risks. We reviewed the fate of DNA derived from GM food in the human body. During mechanical/chemical processing, integrity of DNA is compromised. Food-DNA can survive harsh processing and digestive conditions with fragments up to a few hundred bp detectable in the gastrointestinal tract. Compelling evidence supported the presence of food (also GM food) derived DNA in the blood and tissues of human/animal. There is limited evidence of food-born DNA integrating into the genome of the consumer and of horizontal transfer of GM crop DNA into gut-bacteria. We find no evidence that transgenes in GM crop-derived foods have a greater propensity for uptake and integration than the host DNA of the plant-food. We found no evidence of plant-food DNA function/expression following transfer to either the gut-bacteria or somatic cells. Strong evidence suggested that plant-food-miRNAs can survive digestion, enter the body and affect gene expression patterns. We envisage that this multi-dimensional review will address questions regarding the fate of GM food-derived DNA and gene-regulatory-RNA in the human body.
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http://dx.doi.org/10.1016/j.fct.2018.12.030DOI Listing
February 2019

An imazamox-based herbicide causes apoptotic changes in rat liver and pancreas.

Toxicol Rep 2019 19;6:42-50. Epub 2018 Nov 19.

Department of Toxicology & Forensic Sciences, Faculty Medicine, University of Crete, Heraklion, Greece.

We studied the acute toxicity of an imazamox-based herbicide at 12, 24 and 36 mg/kg body (bw) weight imazamox equivalent dose on the liver and pancreatic tissue in Sprague Dawley rats. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, glucose, calcium as well as creatinine, were determined in blood samples, which were collected after 24, 48 and 72 h exposure. Caspase 3 and anti-insulin expression and immunopositivity were evaluated using in situ hybridization and immunohistochemistry, respectively. The imazamox-based herbicide evaluated in this study induced toxic effects even from the lowest dose tested (12 mg/kg bw). The two highest doses caused a statistically significant cytotoxicity on the Langerhans islet cells. Necrotic and degenerative changes were detected in hepatocytes at the two highest doses. Imazamox is considered to be poorly toxic to the liver. Nevertheless, the imazamox-based herbicide formulation tested here reduced the size of the β-islet cells, induced an elevation in serum glucose and calcium. Our data shows that commercial formulations of imazamox containing various co-formulants can have hepatic and pancreatic toxic effects.
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http://dx.doi.org/10.1016/j.toxrep.2018.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289906PMC
November 2018

Editorial: Toxicity of Pesticides on Health and Environment.

Front Public Health 2018 19;6:268. Epub 2018 Sep 19.

Committee for Independent Research and Information on Genetic Engineering (CRIIGEN), Paris, France.

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http://dx.doi.org/10.3389/fpubh.2018.00268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156543PMC
September 2018

Reply to 'Comments on two recent publications on GM maize and Roundup'.

Sci Rep 2018 09 3;8(1):13339. Epub 2018 Sep 3.

University of Caen, Institute of Biology, EA 2608 and Network on Risks, Quality and Sustainable Environment, MRSH, Esplanade de la Paix, University of Caen, Caen, 14032, Cedex, France.

The opinion expressed by Eriksson and colleagues' fails to recognise that there are no standard experimental designs for academic investigations involving omics analyses of genetically modified crops and that the only valid comparator to determine the effect of the process of transgenesis is a near isogenic variety grown at the same time and location, as was the case in our investigation of NK603 maize. Eriksson does not acknowledge that the quality of the rat liver tissues in our chronic Roundup toxicity study has neither been questioned nor branded as unsuitable for further investigation. In addition, Eriksson fails to appreciate that the statistical methods we used to analyse the liver metabolomics dataset are recognised as appropriate as some of a number of approaches that can be taken. Moreover, Eriksson neglects to mention that the proteomics analysis of the liver tissues highlights structural and functional damage from Roundup exposure. Thus our results are sound and the claims by Eriksson and colleagues of experimental flaws are unfounded.Replying to: Eriksson et al. Sci Rep 8 (2018); https://doi.org/10.1038/s41598-018-30440-7 .
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http://dx.doi.org/10.1038/s41598-018-30751-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120931PMC
September 2018

Comparison of transcriptome responses to glyphosate, isoxaflutole, quizalofop-p-ethyl and mesotrione in the HepaRG cell line.

Toxicol Rep 2018 11;5:819-826. Epub 2018 Aug 11.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, 8th Floor, Tower Wing, Great Maze Pond, London SE1 9RT, United Kingdom.

Use and thus exposure to quizalofop-p-ethyl, isoxaflutole, mesotrione and glyphosate, which are declared as active principles in commercial formulations of herbicides, is predicted to rapidly increase in coming years in an effort to overcome the wide-spread appearance of glyphosate-resistant weeds, especially in fields where glyphosate-tolerant genetically modified crops are cultivated in the USA. Thus, there is an urgent need for an evaluation of metabolic effects of new pesticide ingredients used to replace glyphosate. As the liver is a primary target of chemical pollutant toxicity, we have used the HepaRG human liver cell line as a model system to assess the toxicological insult from quizalofop-p-ethyl, isoxaflutole, mesotrione and glyphosate by determining alterations in the transcriptome caused by exposure to three concentrations of each of these compounds, including a low environmentally relevant dose. RNA-seq data were analysed with HISAT2, StringTie and Ballgown. Quizalofop-p-ethyl was found to be the most toxic of the pesticide ingredients tested, causing alterations in gene expression that are associated with pathways involved in fatty acid degradation and response to alcoholism. Isoxaflutole was less toxic, but caused detectable changes in retinol metabolism and in the PPAR signalling pathway at a concentration of 1 mM. ToxCast data analysis revealed that isoxaflutole activated PPAR gamma receptor and pregnane X responsive elements in reporter gene assays. Glyphosate and mesotrione caused subtle changes in transcriptome profiles, with too few genes altered in their function to allow a reliable pathway analysis. In order to explore the effects of glyphosate in greater depth and detail, we undertook a global metabolome profiling. This revealed a decrease in free long chain fatty acids and polyunsaturated fatty acid levels at the lowest concentration (0.06 μM) of glyphosate, although no effects were detected at the two higher concentrations tested, perhaps suggesting a non-linear dose response. This surprising result will need to be confirmed by additional studies. Overall, our findings contribute to filling the knowledge gap regarding metabolic toxicity that can potentially arise from exposure to these four herbicide active principles.
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http://dx.doi.org/10.1016/j.toxrep.2018.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098220PMC
August 2018

Author Correction: Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide.

Sci Rep 2018 Aug 17;8(1):12572. Epub 2018 Aug 17.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-30760-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098080PMC
August 2018

Evaluation of neonicotinoid insecticides for oestrogenic, thyroidogenic and adipogenic activity reveals imidacloprid causes lipid accumulation.

J Appl Toxicol 2018 12 27;38(12):1483-1491. Epub 2018 Jun 27.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, London, SE1 9RT, UK.

Few studies have investigated non-target effects of neonicotinoid insecticides on mammalian physiology. This is largely due to the widespread perception that their weak affinity for nicotinic acetylcholine receptor subtypes in vertebrates makes mammalian exposures unlikely to pose health risks. To the best of our knowledge, we describe the first investigation evaluating the interaction of seven principal neonicotinoid insecticides (thiamethoxam, imidacloprid, clothianidin, flupyradifurone, dinotefuran, nitenpyram, thiacloprid) with oestrogen and thyroid hormone receptors, as well as their adipogenic effects, in mammalian cell culture assay systems. An E-Screen with MCF-7 and T-Screen with GH3 cells respectively showed a lack of oestrogen and thyroid hormone receptor agonist effects for any of the neonicotinoids tested. Adipogenicity was assessed by the ability to stimulate lipid accumulation in adipocyte differentiated 3T3-L1 cells, with only imidacloprid scoring positive in this assay causing triglyceride accumulation from a concentration of 50 mg l . Data mining of ToxCast high-throughput screening assays revealed that this adipogenic effect of imidacloprid is probably mediated via the pregnane X receptor.
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http://dx.doi.org/10.1002/jat.3651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221087PMC
December 2018

Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126.

Arch Toxicol 2018 08 14;92(8):2533-2547. Epub 2018 Jun 14.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences and Medicine, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.

Chemical pollutant exposure is a risk factor contributing to the growing epidemic of non-alcoholic fatty liver disease (NAFLD) affecting human populations that consume a western diet. Although it is recognized that intoxication by chemical pollutants can lead to NAFLD, there is limited information available regarding the mechanism by which typical environmental levels of exposure can contribute to the onset of this disease. Here, we describe the alterations in gene expression profiles and metabolite levels in the human HepaRG liver cell line, a validated model for cellular steatosis, exposed to the polychlorinated biphenyl (PCB) 126, one of the most potent chemical pollutants that can induce NAFLD. Sparse partial least squares classification of the molecular profiles revealed that exposure to PCB 126 provoked a decrease in polyunsaturated fatty acids as well as an increase in sphingolipid levels, concomitant with a decrease in the activity of genes involved in lipid metabolism. This was associated with an increased oxidative stress reflected by marked disturbances in taurine metabolism. A gene ontology analysis showed hallmarks of an activation of the AhR receptor by dioxin-like compounds. These changes in metabolome and transcriptome profiles were observed even at the lowest concentration (100 pM) of PCB 126 tested. A decrease in docosatrienoate levels was the most sensitive biomarker. Overall, our integrated multi-omics analysis provides mechanistic insight into how this class of chemical pollutant can cause NAFLD. Our study lays the foundation for the development of molecular signatures of toxic effects of chemicals causing fatty liver diseases to move away from a chemical risk assessment based on in vivo animal experiments.
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http://dx.doi.org/10.1007/s00204-018-2235-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063328PMC
August 2018

Sex-dependent impact of Roundup on the rat gut microbiome.

Toxicol Rep 2018 19;5:96-107. Epub 2017 Dec 19.

University of Caen Normandy (UCN), UR ABTE, EA 4651 Boulevard Maréchal Juin, CS 14032 Caen Cedex 5, France.

A growing body of research suggests that dysbiosis of the gut microbiota induced by environmental pollutants, such as pesticides, could have a role in the development of metabolic disorders. We have examined the long-term effects of 3 doses of the Roundup(R) herbicide (made of glyphosate and formulants) on the gut microbiota in male and female Sprague-Dawley rats. A total of 141 bacteria families were identified by a 16S sequencing analysis approach. An OPLS-DA analysis revealed an increased Bacteroidetes family S24-7 and a decreased Lactobacillaceae in 8 out of the 9 females treated with 3 different doses of R (n = 3, for each dose). These effects were confirmed by repetitive sequence-based PCR fingerprinting showing a clustering of treated females. A culture-based method showed that R had a direct effect on rat gut microbiota. Cultivable species showed different sensitivities to R, including the presence of a high tolerant or resistant strain identified as by 16S rRNA sequencing. The high tolerance of this strain was explained by the absence of the EPSPS gene (coding glyphosate target enzyme) as shown by DNA amplification. Overall, these gut microbiome disturbances showed a substantial overlap with those associated with liver dysfunction in other studies. In conclusion, we revealed that an environmental concentration of R (0.1 ppb) and other two concentrations (400 ppm and 5,000 ppm) have a sex-dependent impact on rat gut microbiome composition and thus warrants further investigation.
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http://dx.doi.org/10.1016/j.toxrep.2017.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977165PMC
December 2017
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