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

Chemical monitoring studies in North Carolina, USA and Shandong, China have reported detections of perfluoroalkylether carboxylic acids of increasing chain length with ether bonds between each fluorinated carbon. Despite detection there is 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 18-22 across a series of doses (0.3 - 62.5 mg/kg/d) via oral gavage. PFO5DoA was acutely toxic to rat dams and fetuses at the top two doses (30 and 62.5 mg/kg), while PFO4DA did not cause acute toxicity at any doses tested. PFO5DoA significantly increased maternal liver weight (≥3 mg/kg; 28% increase at 10 mg/kg) while PFO4DA did not affect maternal liver weight up to 62.5 mg/kg. PFO4DA and PFO5DoA both significantly reduced serum total thyroxine in maternal (≥10 mg/kg for both) and fetal (≥1 mg/kg) rats. Both compounds significantly 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 concentrations of PFO5DoA were higher than PFO4DA in both rat dams and fetuses at equivalent maternal oral doses indicating greater accumulation. Dose response modelling of several fetal endpoints as a function of serum molar concentration indicates PFO5DoA was ∼3-4-fold more potent than PFO4DA. PFO5DoA and PFO4DA produced maternal and fetal toxicity from short-term oral maternal exposure indicating need for additional toxicity data to evaluate potential human health risks.