Activation of estrogen-related receptor: An alternative mechanism of hexafluoropropylene oxide homologs estrogenic effects

Perfluorooctanoic acid (PFOA) alternatives such as hexafluoropropylene oxide homologs (HFPOs) cause concern due to increased occurrence in the environment as well as potential bioaccumulation and toxicity. HFPOs have been demonstrated to activate the estrogen receptor (ER) pathway. The ER pathway is homologous and connected to the estrogen-related receptor (ERR) pathway, but HFPOs effects on the ERR pathway have not been studied. Hence, we assessed the potential estrogenic effects of HFPOs via ERR? pathway. In vitro assays revealed that HFPO dimeric, trimeric, and tetrameric acids (HFPO-DA,-TA, and-TeA, respectively), acted as ERR? agonists, activating the transcription of both human and zebrafish ERR? at low concentrations, but inhibiting zebrafish ERR? at high concentrations. We also found that HFPO-TA promoted the human endometrial cancer cells (Ishikawa cells) proliferation via ERR?/EGF, Cyclin D1 pathway. The HFPO-TA-induced proliferation of Ishikawa cells was inhibited by co-exposure with a specific antagonist of ERR?, GSK5182. In vivo exposure of female zebrafish to HFPO-TA disturbed sex hormone levels, interfered with the gene expression involved in estrogen synthesis and follicle regulation, and caused histopathological lesions in the ovaries, which were similar to those induced by a known ERR? agonist GSK4716. Taken together, this study revealed a new mechanism concerning the estrogenic effect of HFPOs via activation of the ERR? pathway.

Automated summary

HFPOs, as alternatives to PFOA, have raised concerns due to their increased occurrence in the environment and potential bioaccumulation and toxicity. This study found that HFPOs can activate the ERR pathway, affecting cell proliferation, sex hormone levels, and ovarian health.