Short chain chlorinated paraffins (SCCPs) disrupt hepatic fatty acid metabolism in liver of male rat via interacting with peroxisome proliferator activated receptor a (PPARa)
Short chain chlorinated paraffins (SCCPs) are frequently detected in environmental matrices and human tissues. It was hypothesized that SCCPs might interact with the peroxisome proliferator activated receptor a (PPARa) In the present study, an in vitro, dual luciferase reporter gene assay and in silico molecular docking analysis were employed together to study the interactions between SCCPs congeners and PPARa. Expressions of genes downstream in pathways activated by PPARa in liver of rats exposed to 1, 10, or 100 mg/kg bm/d of C10 13 CPs (56.5% Cl) for 28 days were examined to confirm activation potencies of SCCPs toward PPARa signaling. Effects of exposure to C10 13 CPs (56.5% Cl) on fatty acid metabolism in rat liver were also explored via a pseudo targeted metabolomics strategy. Our results showed that C10 13 CPs (56.5% Cl) caused a dose dependent greater expression of luciferase activity of rat PPARa. Molecular docking modeling revealed that SCCPs had a strong capacity to bind with PPARa only through hydrophobic interactions and the binding affinity was dependent on the degree of chlorination in SCCPs congeners. In livers of male rats, exposure to 100 mg/kg bm/d of C10 13 CPs (56.5% Cl) resulted in up regulated expressions of 11 genes that are downstream in the PPARa activated pathway and regulate catabolism of fatty acid. Consistently, accelerated fatty acid oxidation was observed mainly characterized by lesser concentrations of fatty acids in livers of rats. Overall, these results demonstrated, for the first time, that SCCPs could activate rat PPARa signaling and thereby disrupt metabolism of fatty acid in livers of male rats.
Ecotoxicology and environmental safety