Tri-ortho-cresyl phosphate causes glucose intolerance and insulin resistance in mice by inducing oxidative stress.

As a typical organophosphorus compound, tri-ortho-cresyl phosphate (TOCP) has been widely used as an industrial additive. But the toxicity of TOCP in the maintenance of glucose homeostasis has not been fully elucidated. In this study, the mechanism of TOCP's effect in glucose homeostasis was investigated using both animal models and cellular experiments. Subchronic exposure to TOCP in ICR mice caused increase of fast glucose level in blood and insulin resistance. In addition, we found significant oxidative stress and downregulation of glucose transporter in liver after TOCP treatment. In pancreas, compensatory pancreatic β-cell hyperplasia was observed. Notably, antioxidant vitamin C cotreatment was able to ameliorate glucose metabolism disorders and reduce oxidative stress in liver in vivo. In the HepG-2 cells, TOCP metabolite CBDP exposure caused decrease of glucose uptake stimulated by insulin, downregulation of glucose transporter gene and accumulation of reactive oxygen species. Vc cotreatment reversed these phenomena. This study demonstrates that organophosphorus exposure can trigger insulin resistance and glucose intolerance through induction of oxidative stress, which provides new insights in the organophosphorus compounds' metabolic toxicity and potential treatment of this toxicity.