Parental exposure to hexafluoropropylene oxide trimer acid induces transgenerational developmental toxicity and thyroid endocrine disruption effects in zebrafish

Hexafluoropropylene oxide trimer acid (HFPO-TA), a novel alternative to perfluorooctanoic acid, has been ubiquitously detected in aquatic environment. However, the current understanding of its transgenerational toxicity in fish and the underlying mechanisms remains scarce. Therefore, in this study, adult zebrafish (F0) were exposed to HFPO-TA at concentrations of 0, 0.5, 5, and 50 g/L for 90 days, and transgenerational developmental toxicity and thyroid disruption effects across three generations were investigated. The results revealed that parental HFPO-TA exposure induced significant reductions of the heart rate and swirl-escape rate in unexposed F1 and F2 offspring, which could be induced by dysregulating genes involved in the central nervous system development and associated with the thyroid hormone (TH) disorders. Furthermore, histological changes of thyroid follicles, disruptions of TH homeostasis and transcriptional expressions of key genes involved in the hypothalamic-pituitary-thyroid axis, and DNA methylation modifications in the promoter of two key genes, were observed across three generations. These suggested that parental HFPO-TA exposure could dysregulate the gene expressions via disrupting DNA methylation in the promoters, and consequently induced the adverse effects. Interestingly, the thyroid disruption effects in F1 offspring were associated with maternal transfer of HFPO-TA and promoter methylation of key genes, while the adverse effects in F2 offspring were associated with maternal transfer of THs as well as promoter methylation of key genes. These findings could promote our understanding on transgenerational toxicity induced by HFPO-TA, and adverse effects after the long-term exposure should be given more attention.