Long-chain perfluoroalkylether carboxylic acids PFO5DoA and PFO4DA alter glucose, bile acid, and thyroid hormone homeostasis in fetal rats from 5-day maternal oral exposure
Recent human and environmental monitoring studies in eastern North Carolina, USA and Shandong, China have reported detections of a homologous series of perfluoroalkylether carboxylic acids of increasing chain length with ether bonds between each fluorinated carbon. Despite detection there is very limited hazard data available to inform risk assessment. Here, we exposed pregnant Sprague-Dawley rats to two of these compounds, perfluoro-3,5,7,9-butaoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA), from gestation days (GD) 18-22 across a series of doses (0.3 – 62.5 mg/kg/d) via oral gavage. PFO5DoA was acutely toxic to rat dams resulting in significant bodyweight loss and fetotoxicity at the top dose (62.5 mg/kg) within the first two days of dosing, while 30 mg/kg also produced a significant reduction in dam bodyweight and some fetal mortality. In contrast, PFO4DA did not cause acute toxicity in dams and fetuses at all doses tested. Further, PFO5DoA increased maternal liver weight (≥3 mg/kg) and reduced fetal bodyweight at 30 mg/kg, while PFO4DA did not affect maternal liver weight or fetal bodyweight up to 62.5 mg/kg. PFO4DA and PFO5DoA both significantly reduced maternal and fetal serum total thyroxine (T4), reduced fetal liver glycogen concentrations, increased fetal serum total bile acids, and altered expression levels of multiple genes associated with glucose metabolism in the fetal liver. Serum total triiodothyronine (T3) was also significantly reduced in maternal and fetal serum by PFO5DoA, but not PFO4DA. A companion manuscript reports data on maternal and fetal liver transcriptomics and maternal serum metabolomics. Overall, PFO5DoA was noticeably more potent for producing adverse effects than PFO4DA based on maternal oral dose. Serum concentrations of PFO5DoA were higher in both rat dams and fetuses than PFO4DA at equivalent maternal oral dose levels indicating greater accumulation potential. Dose response modelling of several fetal endpoints as a function of serum molar concentration indicates PFO5DoA was ~3-4-fold more potent than PFO4DA. Both PFO5DoA and PFO4DA produced maternal and fetal toxicity from short-term oral maternal exposure indicating need for additional toxicity and exposure data to evaluate potential human health risks.