Exposure to Perfluorohexane Sulfonate (PFHxS) Induces Metabolic Disturbances in Lactating Rats and Their Offspring
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Perfluorohexane sulfonate (PFHxS) is an environmental pollutant that can be measured in the blood of infants and children worldwide. Several studies have linked PFHxS exposure to metabolic disorders like non-alcoholic fatty liver disease and increased body mass index in children. However, the mechanism of these observations is unknown. To investigate the metabolic effects of PFHxS during development, pregnant Long Evans rats were orally gavaged daily with 0, 17, or 50 mg/kg PFHxS from gestational day 6 to postnatal day 14 (PN14) and the dams and offspring were evaluated. No significant changes in body and liver weights were observed in either the dams or pups. Serum biochemistry revealed that glucose was significantly increased in dams exposed to 50 mg/kg/day PFHxS. With regards to liver and kidney function, significant increases in serum alanine transaminase (ALT) and creatinine (Cr) were detected in dams exposed to 17 mg/kg PFHxS, while those exposed to 50 mg/kg PFHxS showed significant increases in blood urea nitrogen (BUN). Male pups exposed to 50 mg/kg PFHxS exhibited significantly lower serum total protein and globulin levels on PN14. Since the liver is an established target of perfluorinated compounds and controls energy metabolism, we next performed RNA-Sequencing (RNA-Seq) of male pup livers on PN2 and PN14 (0 versus 50 mg/kg PFHxS). RNA-Seq identified 198 and 418 differentially expressed genes (DEGs) on PN2 and PN14, respectively (FDR q<0.05). Pathway analyses showed an enriched signal for ketogenesis, fatty acid oxidation, and peroxisome proliferator-activated receptor (PPAR) activation at both developmental stages. To validate the RNA-Seq findings, we next performed qRT-PCR of male and female littermates from all exposure groups, assaying candidate DEGs related to energy and hormone metabolism. Our results demonstrate agreement between RNA-Seq and qRT-PCR, and agreement between the sexes; additionally, these candidate genes displayed a clear dose response. Taken together, these data suggest PFHxS exposure altered glucose metabolism in dams, and serum protein content in the pups. In addition, a transcriptomic signature consistent with abnormal energy processing was identified in the male pup liver. This work does not reflect US EPA policy.