Exposure to short-chain chlorinated paraffins inhibited PPARα-mediated fatty acid oxidation and stimulated aerobic glycolysis in vitro in human cells.

Abstract Short-chain chlorinated paraffins (SCCPs) could disrupt fatty acid metabolism in male rat liver through activating rat PPARα signaling. However, whether this mode of action can translate to humans remained largely unclear. In this study, based on luciferase assays, C10−13-CPs (56.5% Cl) at concentrations greater than 1 μM (i.e., 362 μg/L) showed weak agonistic activity toward human PPARα (hPPARα) signaling. But in HepG2 cells, exposure to C10−13-CPs (56.5% Cl) at the human internal exposure level (100 μg/L) down-regulated expressions of most of the tested hPPARα target genes, which encode for enzymes that oxidize fatty acids. In line with the gene expression data, metabolomics further confirmed that exposure to four SCCP standards with varying chlorine contents at 100 μg/L significantly suppressed oxidation of fatty acids in HepG2 cells, mainly evidenced by elevations in both total fatty acids and long-chain acylcarnitines. In addition, exposure to these SCCPs also caused a shift in carbohydrate metabolism from the tricarboxylic acid cycle (TCA cycle) to aerobic glycolysis. Overall, the results revealed that SCCPs could inhibit hPPARα-mediated fatty acid oxidation, and stimulated aerobic glycolysis in HepG2 cells.