Maternal Exposure to Perfluorohexane Sulfonate (PFHxS) Alters Glucose and Lipid Dynamics During the Postnatal Period in the Rat

Perfluorohexane sulfonate (PFHxS) is a ubiquitous environmental contaminant that can be quantified in the sera of infants, children, and adults throughout the United States. Some epidemiological studies have correlated PFHxS exposure to metabolic dysfunction like gestational diabetes and increased body mass index in children. However, the mechanism(s) of such effects are unclear. To determine if PFHxS may alter lipid and glucose metabolism during development, pregnant Long Evans rats were dosed orally with 0, 17, or 50 mg/kg/d of PFHxS from gestational day (GD) 2 to postnatal day (PND) 14 and the dams and offspring evaluated. Neither body nor liver weights were significantly different in PFHxS exposed dams and/or pups relative to controls. PFHxS exposure significantly decreased total cholesterol in dams on PND14. Serum glucose was increased, and this was statistically significant following the 50 mg/kg/d exposure. Given that the liver is a major metabolic regulator and a known target of other perfluoroalkyl substances, we next performed RNA-Seq of liver tissue in male pups on PND2 and PND14 (0 versus 50 mg/kg/d PFHxS). RNA-Seq identified 198 and 416 differentially expressed genes on PND2 and PND14 respectively (q<0.05). Pathway analyses showed an enriched signature for increased fatty acid oxidation and ketogenesis at both developmental stages. Next, we validated our RNA-Seq data by performing qRT-PCR for top candidate genes in both male and female littermates. Our results showed concordance between RNA-Seq and qRT-PCR and between the sexes; in addition, these candidate genes exhibited a dose response. Together these data suggest developmental exposure to PFHxS alters lipid and glucose metabolism in the mothers, and the hepatic transcriptome in offspring. While the dams exhibited increased serum glucose, the pup liver showed a clear signature of increased insulin sensitivity. While exposed animals did not show a change in overall bodyweight, we are currently investigating changes in maternal and offspring body composition throughout the lifespan.  This work does not reflect US EPA policy.

Impact/Purpose

Some perfluoroalkyl substances (PFAS) have been associated with metabolic dysfunction in human populations, including children. Here we studied if a maternal exposure to perfluorohexane sulfonate (PFHxS) may alter lipid and glucose metabolism during lactation and postnatal development in the rat. Pregnant rats were dosed with either vehicle control (water), a low dose of perfluorohexane sulfonate (PFHxS, 17 mg/kg/day), or a high dose (50 mg/kg/day) throughout pregnancy and the postnatal period. Our data show that maternal PFHxS exposure significantly increased dam serum glucose following the high dose exposure. We next examined the pup liver at two developmental stages as the liver is a known target of some PFAS, and is a major metabolic regulator. RNA-Sequencing (RNA-Seq) of the liver on postnatal days 2 and 14 show a strong transcriptional signal reflective of increased ketogenesis and fatty acid oxidation, which suggests that the pups may exhibit increased insulin sensitivity. Together, these data show that while dam glucose is higher postpartum, the opposite signal is observed in their offspring. The long-term consequences of these metabolic changes are not known, but we are next testing how PFHxS changes body composition in mothers and their offspring overtime. These data support the Agency’s PFAS Action Plan and can aid risk assessors in interpreting the health effects of PFHxS.

Citation

O'Shaughnessy, K., K. Bell, A. Sasser, C. Miller, G. Jung, D. Jenkins-Hill, C. Wood, M. Strynar, AND J. McCord. Maternal Exposure to Perfluorohexane Sulfonate (PFHxS) Alters Glucose and Lipid Dynamics During the Postnatal Period in the Rat. Society of Toxicology Annual Meeting, Nashville, TN, March 19 - 23, 2023.