GSE212294
Transcriptional profilling of liver from C57BL/6 wildtype and PPARa-knockout mice treated with PFOA and GenX after 20 weeks of high-fat diet
Perfluoroalkyl substances (PFAS) are man-made chemicals with suspected endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic effects of the new PFAS alternative GenX is limited. We tested whether low-dose exposure to PFOA and GenX induces metabolic disturbances, including NAFLD, dyslipidemia, and glucose tolerance in mice and studied the involvement of PPARa. To this end, male C57BL/6J wildtype and PPARa-/- mice were given 0.05 or 0.3 mg/kg bw/day PFOA, or 0.3 mg/kg bw/day GenX next to a high-fat diet for 20 weeks. RNA sequencing was performed on liver, next to thorough assesment of metabolic parameters. RNA sequencing revealed that whereas the effects of GenX are entirely dependent on PPARa, effects of PFOA are mostly dependent on PPARa. In the absence of PPARa, the involvement of PXR/CAR becomes more prominent. Exposure to high-dose PFOA in mice decreased body weights and increased liver weights in wildtype and PPARa-/- mice. High-dose but not low-dose PFOA reduced plasma triglycerides and cholesterol, which for triglycerides, showed PPARa dependency. PFOA and GenX increased hepatic triglycerides in a PPARa-dependent manner. Overall, we show that long-term and low-dose exposure to PFOA and GenX disrupts lipid metabolism in mice. Whereas the effects of PFOA are mediated by multiple nuclear receptors, effects of GenX are entirely mediated by PPARa. Our data underscore the potential of PFAS to disrupt metabolism by altering signaling pathways in the liver. Overall design: Comparative gene expression profiling analysis of RNA-seq data from livers of male C57BL/6 wildtype and PPARa-knockout mice treated with 0.05 mg/kg bw/day or 0.3 mg/kg bw/day PFOA, or 0.3 mg/kg bw/day next to a high-fat diet for 20 weeks (n=4/group).