Gul Sahika Gokdemir, Sevda Canbay Durmaz, Selim Demirtaş, Nazan Baksi, Mehmet Tahir Gokdemir
Glyphosate-based herbicides (GBHs) are widely used worldwide. Increasing evidence has raised concerns about their hepatotoxic effects. While oxidative stress, inflammation, and apoptosis contribute to glyphosate-induced liver damage, the roles of intracellular cyclic nucleotides and vascular endothelial growth factor (VEGF) are not fully understood. This study investigated the dose-dependent effects of glyphosate on liver function, oxidative status, intracellular cyclic nucleotides, inflammatory mediators, apoptotic markers, and VEGF in adult female Wistar rats. Twenty-eight female Wistar rats were randomly assigned to four groups (n = 7/group) and administered orally either distilled water (control) or glyphosate at doses of 250, 500, or 1000 mg/kg/day for 30 days. Serum aminotransferase activities and total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), caspase-3, VEGF, Bax/Bcl-2 immunoreactivity, and histopathological changes were evaluated. Dose-response relationships were assessed using polynomial trend analysis. Glyphosate exposure caused dose-dependent increases in AST, TOS, OSI, TNF-α, IL-1β, caspase-3, VEGF, and the Bax/Bcl-2 ratio, accompanied by decreases in TAS, cAMP, and cGMP, as well as progressive histopathological changes. Polynomial trend analysis showed significant linear dose-response relationships for all biomarkers, while OSI, caspase-3, VEGF, and the Bax/Bcl-2 ratio showed significant deviations from linearity at higher glyphosate doses. These findings suggest that glyphosate-induced hepatotoxicity is associated with coordinated alterations in oxidative status, intracellular cyclic nucleotide homeostasis, inflammatory responses, apoptosis, and hepatic VEGF levels.