Maternal, fetal, and neonatal toxicity and potency estimates of perfluorohexane sulfonate (PFHxS) from oral maternal exposure in the Sprague-Dawley rat

Perfluorohexane sulfonate (PFHxS) is a legacy, long-chain per- and polyfluoroalkyl substance (PFAS) frequently detected in human serum and environmental media across the globe. Previously published developmental studies in rats indicated a general lack of effects in common endpoints like maternal and offspring body and liver weights at doses up to 50 mg/kg/d. To facilitate mixture-based studies of PFAS co-exposure, individual dose response parameters are necessary for model predictions. To address these data needs we exposed timed-pregnant Sprague-Dawley rat dams to PFHxS (3–125 mg/kg/d) via oral gavage from gestation days (GD)14–18 or GD8 to postnatal day (PND)2. We evaluated a range of key events and adverse outcomes in both exposure intervals with a focus on chemical effects on serum thyroid hormone concentrations and liver toxicity. Maternal exposure from GD14–18 resulted in increased maternal liver weight (≥30 mg/kg), reduced serum total thyroxine (T4; ≥10 mg/kg) and low-density lipoprotein (LDL; ≥10 m/kg), and modest changes in maternal liver fatty acid metabolism-associated and fetal liver peroxisome proliferator-activated receptor signaling-associated gene expression. Exposure from GD8-PND2 did not affect newborn liver glycogen concentration, but did result in other neonatal effects consistent with prior PFAS studies including reduced pup survival (125 mg/kg), reduced pup bodyweight (≥62.5 mg/kg), increased pup liver weight (≥10 mg/kg), highly elevated pup serum total cholesterol and bile acids (≥3 mg/kg) and reduced serum thyroid hormones (T3, rT3, T4; ≥3 mg/kg). Maternal effects were largely limited to reductions in serum total T3 and T4 (≥10 mg/kg) and elevated serum BUN (≥62.5 mg/kg). Compared to previously published data for other PFAS, PFHxS displayed relatively low potency as a function of maternal serum concentration across a range of effects.