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

Whether or not glyphosate activates cellular mechanisms involved in
carcinogenesis remains controversial. We tested whether
glyphosate and three glyphosate-based commercial herbicide
formulations activate mechanisms known to be key characteristics
of carcinogens. The mammalian stem cell-based
genotoxicity ToxTracker assay showed that the
representative EU formulation Roundup MON 52276 and the UK
formulation Roundup MON 76473, but not glyphosate and the US
Roundup formulation MON 76207, activated oxidative stress and
unfolded protein responses. High-throughput molecular profiling of liver
function was performed in female Sprague-Dawley rats exposed to
glyphosate or MON 52276 (both at 0.5, 50, 175 mg/kg bw/day glyphosate
equivalent concentration) for 90 days. Histopathology
and serum biochemistry analysis showed that MON 52276 but not
glyphosate treatment increased hepatic steatosis and necrosis. MON 52276
and glyphosate altered the expression of genes in liver reflecting TP53
activation by DNA damage and the regulation of circadian
rhythms. The most affected genes in liver also had their
expression similarly altered in kidneys. Small RNA profiling in
liver showed miR-22 and miR-17 had their levels decreased by MON
52276, while mir-30 levels were decreased, whilst miR-10 levels were
increased by glyphosate. DNA methylation profiling of liver
revealed 5,727 and 4,496 differentially methylated CpG sites between the
control and glyphosate and MON 52276 exposed groups of animals
respectively. Direct DNA damage measurement by
apurinic/apyrimidinic lesion formation in liver was increased with
glyphosate exposure. Altogether, our results show that Roundup herbicide
formulations are causing more biological changes than glyphosate alone,
activating mechanisms involved in cellular carcinogenesis.