Toxicological mechanisms of emerging per-/poly-fluoroalkyl substances: Focusing on transcriptional activity and gene expression disruption

Environmental and human monitoring studies have witnessed increasing occurrence of emerging per-/poly-fluoroalkyl substances (ePFASs) worldwide. Three classes of ePFASs, namely chlorinated polyfluoroalkylether sulfonic acids, hexafluoropropylene oxide homologues and short-chain perfluoroalkyl acids attracted the most attention. It is, therefore, the goal of this review to systematically and critically analyse the toxicity and toxicological mechanisms of these ePFASs based on the papers published between 2017 and 2022. The review summarized the main findings from both in vivo and in vitro studies, covering the hepatotoxicity of ePFASs and their interference with the endocrine system, including reproductive, developmental and thyroid toxicity. It also summarized the changes in gene expression in the hypothalamic-pituitary-thyroid axis and hypothalamic-pituitary-gonad axis of the model organisms after ePFASs exposure. The changes in gene expression in vitro and in vivo provide a clearer understanding of the toxicological mechanisms of ePFASs interference on hormonal levels (i.e., estradiol, testosterone, and thyroid hormones), developmental disturbance (e.g., swim bladder dysfunction) and lipid metabolism disruption (e.g., lipid droplet accumulation and hepatomegaly). In the end, future research directions on the toxicological mechanisms of ePFASs are suggested.

Automated summary

This review systematically and critically analyzes the toxicity and toxicological mechanisms of emerging per-/poly-fluoroalkyl substances (ePFASs), including chlorinated polyfluoroalkylether sulfonic acids, hexafluoropropylene oxide homologues, and short-chain perfluoroalkyl acids. The main findings from in vivo and in vitro studies are summarized, covering the hepatotoxicity of ePFASs, their interference with the endocrine system, and changes in gene expression in model organisms. These findings provide a clearer understanding of the toxicological mechanisms of ePFASs on hormonal levels, developmental disturbance, and lipid metabolism disruption. Future research directions on ePFASs toxicological mechanisms are suggested.