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

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

  • Sci Total Environ. 2023 Aug 11;166257. doi: 10.1016/j.scitotenv.2023.166257.
Lu Chen 1,  Xicha Lin 2,  Sha Shi 3,  Minjie Li 4,  Monika Mortimer 5,  Wendi Fang 6,  Fangfang Li 7,  Liang-Hong Guo 8
Affiliations

Affiliations

  • 1 College of Life Sciences, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China; Institute of Environmental and Health Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang 310018, China. Electronic address: s20090710005@cjlu.edu.cn.
  • 2 College of Life Sciences, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China; Institute of Environmental and Health Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang 310018, China. Electronic address: p22091055035@cjlu.edu.cn.
  • 3 College of Life Sciences, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China; Institute of Environmental and Health Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang 310018, China. Electronic address: p22091055043@cjlu.edu.cn.
  • 4 College of Quality and Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China. Electronic address: mjli@cjlu.edu.cn.
  • 5 Institute of Environmental and Health Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang 310018, China; College of Quality and Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China. Electronic address: mmortimer@cjlu.edu.cn.
  • 6 Institute of Environmental and Health Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang 310018, China; College of Quality and Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China. Electronic address: wendifang@cjlu.edu.cn.
  • 7 Institute of Environmental and Health Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang 310018, China; College of Quality and Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China. Electronic address: liff@cjlu.edu.cn.
  • 8 Institute of Environmental and Health Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang 310018, China; College of Quality and Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China. Electronic address: lhguo@cjlu.edu.cn.
PMID: 37574057 DOI: 10.1016/j.scitotenv.2023.166257
Abstract

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 ERRγ pathway. In vitro assays revealed that HFPO dimeric, trimeric, and tetrameric acids (HFPO-DA, -TA, and -TeA, respectively), acted as ERRγ agonists, activating the transcription of both human and zebrafish ERRγ at low concentrations, but inhibiting zebrafish ERRγ at high concentrations. We also found that HFPO-TA promoted the human endometrial Cancer cells (Ishikawa cells) proliferation via ERRγ/EGF, Cyclin D1 pathway. The HFPO-TA-induced proliferation of Ishikawa cells was inhibited by co-exposure with a specific antagonist of ERRγ, 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 ERRγ Agonist GSK4716. Taken together, this study revealed a new mechanism concerning the estrogenic effect of HFPOs via activation of the ERRγ pathway.

Keywords

Estrogen-related receptor γ; Estrogenic effect; Hexafluoropropylene oxide; Ishikawa cell; Ovarian damage.

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