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In-depth comparative toxicogenomics of glyphosate and Roundup herbicides: histopathology, transcriptome and epigenome signatures, and DNA damage

Robin Mesnage, Mariam Ibragim, Daniele Mandrioli, Laura Falcioni, Fiorella Belpoggi, Inger Brandsma, Emma Bourne, Emanuel Savage, Charles A Mein, Michael N Antoniou
doi: https://doi.org/10.1101/2021.04.12.439463
Robin Mesnage
1Gene 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
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Mariam Ibragim
1Gene 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
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Daniele Mandrioli
2Cesare Maltoni Cancer Research Center, Ramazzini Institute (RI), Via Saliceto, 3, 40010 Bentivoglio, Bologna, Italy
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Laura Falcioni
2Cesare Maltoni Cancer Research Center, Ramazzini Institute (RI), Via Saliceto, 3, 40010 Bentivoglio, Bologna, Italy
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Fiorella Belpoggi
2Cesare Maltoni Cancer Research Center, Ramazzini Institute (RI), Via Saliceto, 3, 40010 Bentivoglio, Bologna, Italy
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Inger Brandsma
3Toxys, Robert Bolyeweg 4, 2333 CG, Leiden, The Netherlands
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Emma Bourne
4Genome Centre, Barts and the London School of Medicine and Dentistry, Blizard Institute, London E1 2AT, United Kingdom
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Emanuel Savage
4Genome Centre, Barts and the London School of Medicine and Dentistry, Blizard Institute, London E1 2AT, United Kingdom
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Charles A Mein
4Genome Centre, Barts and the London School of Medicine and Dentistry, Blizard Institute, London E1 2AT, United Kingdom
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Michael N Antoniou
1Gene 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
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  • For correspondence: michael.antoniou@kcl.ac.uk
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Abstract

Background Health effects from exposure to glyphosate-based herbicides is an intense matter of debate. Toxicity including genotoxicity of glyphosate alone has been repeatedly tested over the last 40 years. Contrastingly, few studies have conducted comparative investigations between glyphosate and its commercial herbicide formulations, such as Roundup. We thus performed the first in-depth comparative toxicogenomic evaluation of glyphosate and a typical European Union Roundup formulation by determining alterations in transcriptome and epigenome profiles.

Methods Glyphosate and the European Union reference commercial formulation Roundup MON 52276 (both at 0.5, 50, 175 mg/kg bw/day glyphosate equivalent concentration) were administered to rats in a subchronic 90-day toxicity study. Standard clinical biochemistry and kidney and liver histopathology was performed. In addition, transcriptomics and DNA methylation profiling of liver and selective gene expression analysis of kidneys was conducted. Furthermore, a panel of six mouse embryonic reporter stem cell lines validated to identify carcinogenic outcomes (DNA damage, oxidative stress, and protein misfolding) were used to provide insight into the mechanisms underlying the toxicity of glyphosate and 3 Roundup formulations.

Results Histopathology and serum biochemistry analysis showed that MON 52276 but not glyphosate treatment was associated with a statistically significant increase in hepatic steatosis and necrosis. Similar lesions were also present in the liver of glyphosate-treated groups but not in the control group. MON 52276 altered the expression of 96 genes in liver, with the most affected biological functions being TP53 activation by DNA damage and oxidative stress as well as the regulation of circadian rhythms. The most affected genes in liver also had their expression similarly altered in kidneys. DNA methylation profiling of liver revealed 5,727 and 4,496 differentially methylated CpG sites between the control group and the group of rats exposed to glyphosate and MON 52276, respectively. Direct DNA damage measurement by apurinic/apyrimidinic lesion formation in liver was increased with glyphosate exposure. Mechanistic evaluations showed that two Roundup herbicides but not glyphosate activated oxidative stress and misfolded protein responses.

Conclusions Taken together, the results of our study show that Roundup herbicides are more toxic than glyphosate, activating mechanisms involved in cellular carcinogenesis and causing gene expression changes reflecting DNA damage. This further highlights the power of high-throughput ‘omics’ methods to detect metabolic changes, which would be missed by relying solely on conventional biochemical and histopathological measurements. Our study paves the way for future investigations by reporting a panel of gene expression changes and DNA methylation sites, which can serve as biomarkers and potential predictors of negative health outcomes resulting from exposure to glyphosate-based herbicides.

Competing Interest Statement

RM has served as a consultant on glyphosate risk assessment issues as part of litigation in the US over glyphosate health effects. The other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 13, 2021.
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In-depth comparative toxicogenomics of glyphosate and Roundup herbicides: histopathology, transcriptome and epigenome signatures, and DNA damage
Robin Mesnage, Mariam Ibragim, Daniele Mandrioli, Laura Falcioni, Fiorella Belpoggi, Inger Brandsma, Emma Bourne, Emanuel Savage, Charles A Mein, Michael N Antoniou
bioRxiv 2021.04.12.439463; doi: https://doi.org/10.1101/2021.04.12.439463
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In-depth comparative toxicogenomics of glyphosate and Roundup herbicides: histopathology, transcriptome and epigenome signatures, and DNA damage
Robin Mesnage, Mariam Ibragim, Daniele Mandrioli, Laura Falcioni, Fiorella Belpoggi, Inger Brandsma, Emma Bourne, Emanuel Savage, Charles A Mein, Michael N Antoniou
bioRxiv 2021.04.12.439463; doi: https://doi.org/10.1101/2021.04.12.439463

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