Sub-chronic exposure to Tris(1,3-dichloro-2-propyl) phosphate induces sex-dependent hepatotoxicity in rats

As the application and environmental release of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) are being increased rapidly, serious concerns have been raised regarding its adverse effects on human health. Exposure to TDCIPP has been implicated in hepatotoxicity, but the molecular mechanisms remain unclear. Here, both male and female Sprague Dawley rats were administered TDCIPP with 125, 250, or 500 mg/kg/day for 12 weeks. Then the ultrastructure of liver, biochemical indicators in serum and liver, and hepatic gene expression were analyzed to reveal molecular mechanisms of hepatotoxicity induced by TDCIPP. Continuous TDCIPP exposure decreased body weight, particularly in 500 mg/kg/day TDCIPP-exposed males, and dose dependently increased the ratio of liver to body weight in both genders. The decreased levels of triglyceride, cholesterol, and transaminase in the serum and livers were observed in both genders after TDCIPP exposure, which indicated dysfunction in the hepatic metabolism. Liver histopathology revealed hepatocellular damages in males and females after TDCIPP exposure. The transcriptomic analysis indicated that TDCIPP exposure significantly changed pathways of bile acid metabolism, inflammatory response, oxidative phosphorylation and carcinogenicity in 250 and 500 mg/kg/day TDCIPP-exposed males and 500 mg/kg/day TDCIPP-exposed females, and there was no statistical significance in any other TDCIPP-exposed groups. The transcriptional analysis showed that TDCIPP exposure led to oxidative stress in the livers of rats, thereby increasing the inflammatory response and promoting mechanisms of carcinogenesis in both genders. Finally, TDCIPP led to more severe adverse phenotypic effects in male than female rats.