Chronic exposure to PFO4DA and PFO5DoDA, two perfluoroalkyl ether carboxylic acids (PFECAs), suppresses hepatic stress signals and disturbs glucose and lipid metabolism in male mice.

Perfluoroalkyl ether carboxylic acids (PFECAs), including PFO4DA and PFO5DoDA, have been found in both surface water and volunteer blood samples from polluted regions. However, little knowledge is available on their potential bioaccumulation and health risk. In the present study, the half-lives of PFO4DA and PFO5DoDA in male mouse serum were 24 h and nearly 43 d, respectively, indicating markedly increased difficulty in eliminating PFO5DoDA from the body. After 140 d daily exposure both PFO4DA and PFO5DoDA (10 μg/kg/d) increased body weight. Hepatomegaly was the most sensitive phenomenon after exposure treatment, with occurrence even in the 2 μg/kg/d exposure groups. RNA-seq analysis supported a similar but stronger effect of PFO5DoDA compared with PFO4DA. A wide array of genes involved in stimulus sensing and response were suppressed. In addition to weight gain, hyperglycemia was also observed after treatment. Increased glucose and decreased pyruvate and lactate levels in the liver supported a reduction in glycolysis, consistent with the reduction in the key regulator Pfkfb3. In conclusion, chronic PFO4DA and PFO5DoDA exposure suppressed stress signals and disturbed glucose and lipid metabolism in the liver. The longer serum half-life and stronger hepatic bioaccumulation of PFO5DoDA, at least partially, contributed to its stronger hepatotoxicity than that of PFO4DA.