ORIGINAL ABSTRACT

Glyphosate, the most extensively applied organophosphonate herbicide, poses risks to aquatic ecosystems and potentially compromises human health via dietary exposure. Although toxicological assessments have confirmed glyphosate-induced hepatotoxicity in mammalian systems, the cellular pathogenesis involving metabolic disruption warrants further mechanistic investigation. This study aimed to elucidate the effect of glyphosate exposure on hepatic glucose/lipid metabolism and its association with circadian clock disruption using murine hepatocytes (AML12) and mice models. Time-course analysis revealed that glyphosate exposure significantly suppressed core circadian and metabolic transcripts in AML12 hepatocytes, with corresponding reduction in NR1D1 protein level. Longitudinal locomotor activity monitoring revealed that glyphosate exposure caused photophase-specific hyperlocomotion and circadian period elongation in mice. Glyphosate exposure elicited marked depletion of hepatic glycogen reserves and serum total cholesterol concentrations. Notably, glyphosate also disrupted the expression of hepatic metabolic genes, paralleled by alterations of circadian clock genes expression at both mRNA and protein levels in mice. Additionally, Hmgcr and Glut2 mRNA levels were significantly decreased in Bmal1-/- AML12 cells compared to their control groups, no further significant reduction was detected in Bmal1-/- AML12 cells with glyphosate exposure. Collectively, the current study demonstrated that glyphosate exposure impairs glucose and lipid metabolism by disturbing the circadian clock system.