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.

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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.