Thiamethoxam induced hepatotoxicity and pro-carcinogenicity in rabbits via motivation of oxidative stress, inflammation, and anti-apoptotic pathway

Thiamethoxam (TMX) is a non-mutagenic neonicotinoid insecticide that is widely used to combat different types of insects. The hepatotoxicity and carcinogenicity of TMX have been approved previously in mice but not in rats. However, the TMX-induced hepatotoxic and pro-carcinogenic effects on rabbits remain unclear. The present study elucidated the roles of oxidative stress, pro-inflammatory cytokines, and apoptosis-related genes in the hepatotoxic and carcinogenic effects of TMX on rabbits. Sixteen male rabbits were equally divided into two groups; eight rabbits orally treated with TMX at a dose of 250 mg/kg b.w for 90 successive days. Hepatotoxic effects of TMX were evidenced by attenuation of liver enzyme activities, elevation of bilirubin levels, and alterations in the hepatic architecture, including hepatocyte death by necrosis and apoptosis, lymphocyte infiltration and fibrosis. TMX induced oxidative stress, as evidenced by the significant increases in malondialdehyde levels and antioxidant enzyme (glutathione transferase and catalase) activities along with a decrease in glutathione levels. TMX also up-regulated the mRNA levels of interleukin-6 (1.6-fold) and B cell lymphoma-2 (1.8-fold) and down-regulated the mRNA level of the tumor necrosis factor-alpha (0.8-fold), indicating its effects on cell survival and proliferation through the inhibition of apoptosis. Interestingly, the elevated level of carcinoembryonic antigen and the appearance of ground glass-like hepatocytes suggested that TMX exerted a pro-carcinogenic effect. In conclusion, TMX exerts potentially hepatotoxic and pro-carcinogenic effects on rabbits by modulating oxidative/antioxidative status and pro-inflammatory cytokine production, inhibiting apoptosis and activating cell survival pathways.