Effects of Chemical Speciation on Chronic Thyroid Toxicity of Representative Perfluoroalkyl Acids

Acute exposure studies have reported that chemical speciation significantly affects the developmental toxicity of perfluoroalkyl acids (PFAAs). However, the mechanisms underlying the chronic toxicity of PFAAs as a function of chemical speciation remain unknown. With an aim to gain more insights into the PFAA structure-toxicity relationship, this study exposed adult zebrafish to the acids and salts of perfluorooctanoate (PFOA), perfluorobutanoate (PFBA), and perfluorobutanesulfonate (PFBS) at environmentally realistic concentrations for 5 months. In the F0 generation, PFAA acids induced hypothyroidism symptoms more potently than their salt counterparts. After parental exposure, a chemical speciation-dependent transfer behavior was noted, with a greater burden of PFAA acids in the offspring. Similarly, PFAA acids were associated with higher risks of transgenerational defects and thyroid dysfunction during offspring embryogenesis. PFAA acids bound to thyroid receptor beta (TRβ) more strongly than their salts. An antagonistic interaction of PFOA and PFBS with TR activity was observed in vitro via the reduction of TRβ accessibility to target genes. CUT&Tag sequencing revealed disturbances due to PFAAs on the genomic target profile of TRβ, indicating that PFOA and PFBS interfere with multiple thyroidal and nervous processes. In conclusion, current findings provided evidence regarding the critical effects of chemical speciation on PFAA toxicity, highlighting the need to perform discriminative risk assessment and chemical management. © 2025 American Chemical Society.