Accumulation and glucocorticoid signaling suppression by four emerging perfluoroethercarboxylic acids based on animal exposure and cell testing

Various perfluoroethercarboxylic acids (PFECA) have emerged as next-generation replacements of legacy per- and polyfluoroalkyl substances (PFAS). However, there is a paucity of information regarding their bioaccumulation ability and hazard characterization. Here, we explored the accumulation and hepatotoxicity of four PFECA compounds (HFPO-DA, HFPO-TA, PFO4DA, and PFO5DoDA) in comparison to perfluorooctanoic acid (PFOA) after chronic low-dose exposure in mice. Except for HFPO-DA, the levels of all tested PFAS in the liver exceeded that in serum. High molecular weight PFECA compounds (PFO5DoDA and HFPO-TA) showed stronger accumulation capacity and longer half-lives (t_1/2) than low molecular weight PFECA compounds (HFPO-DA and PFO4DA) and even legacy PFOA. Although hepatomegaly is a common apical end point of PFAS exposure, the differentially expressed gene (DEG) profiles in the liver suggested significant differences between PFOA and the four PFECA compounds. Gene enrichment analysis supported a considerable inhibitory effect of PFECA, but not PFOA, on the glucocorticoid receptor (GR) signaling pathway. Both HFPO-TA and PFO5DoDA demonstrated a more pronounced ability to perturb RNA expression profiles in vivo and to suppress GR signaling in vitro compared to HFPO-DA and PFO4DA. Calculated reference doses (RfDs) emphasized the potential hazard of PFECA to human health. Overall, our findings indicate that PFECA alternatives do not ease the concerns raised from legacy PFAS pollution.