title: Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide.
abstract: The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure.
authors.affiliation: 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.
authors.forename: Robin
authors.initials: R
authors.lastname: Mesnage
authors.affiliation: Proteomics Facility, King's College London, Institute of Psychiatry, London SE5 8AF, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Renney
authors.affiliation: University of Caen, Institute of Biology, EA 2608 and Risk Pole, MRSH-CNRS, Esplanade de la Paix, University of Caen, Caen 14032, Cedex, France.
authors.forename: Gilles-Eric
authors.initials: GE
authors.lastname: Séralini
authors.affiliation: Proteomics Facility, King's College London, Institute of Psychiatry, London SE5 8AF, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ward
authors.affiliation: 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.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Antoniou
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D006540:Herbicides / Q000633:toxicity*; D008099:Liver / Q000473:pathology*; D055432:Metabolomics; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000473:pathology*; D040901:Proteomics; D051381:Rats; D000097797:Glyphosate
chemical_list: D005998:Glycine; D006540:Herbicides; D000097797:Glyphosate