Estrogenic and transgenerational effects of perfluorocarboxylic acids through estrogen-related receptor γ pathway

Sha Shi; Wei Zheng; Xi-Long Zhang; Minjie Li; Cheng Ye; Lu Chen; Wen-Jun Hong; Chuan-Hai Li; Huiyu Chi; Fangfang Li; Liang-Hong Guo

doi:10.1016/j.jhazmat.2025.138994

Estrogenic and transgenerational effects of perfluorocarboxylic acids through estrogen-related receptor γ pathway

J Hazard Mater. 2025 Jun 18:495:138994. doi: 10.1016/j.jhazmat.2025.138994. Online ahead of print.

Authors

Sha Shi¹, Wei Zheng¹, Xi-Long Zhang², Minjie Li³, Cheng Ye⁴, Lu Chen¹, Wen-Jun Hong², Chuan-Hai Li⁵, Huiyu Chi², Fangfang Li⁶, Liang-Hong Guo⁷

Affiliations

¹ College of Life Sciences, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China.
² College of Energy Environment and Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China.
³ College of Energy Environment and Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China; Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
⁴ Zhejiang Jiaoke Environmental Technology Co, Ltd., Hangzhou, Zhejiang 311305, China.
⁵ School of Environment, Hangzhou Institute for Advanced Study, University of the Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China.
⁶ College of Energy Environment and Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China. Electronic address: liff@cjlu.edu.cn.
⁷ College of Energy Environment and Safety Engineering, China Jiliang University, 258 Xueyuan Street, Hangzhou, Zhejiang 310018, China; School of Environment, Hangzhou Institute for Advanced Study, University of the Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China. Electronic address: lhguo@ucas.ac.cn.

PMID: 40555023
DOI: 10.1016/j.jhazmat.2025.138994

Abstract

The estrogen-disrupting effects and mechanism of perfluorocarboxylic acids (PFCAs), with similar structures to perfluorooctanoic acid (PFOA), are poorly understood. The purpose of the present study is to explore the estrogen-disrupting effects of PFCAs through the estrogen-related receptor γ (ERRγ) pathway. In vitro, similar to an ERRγ agonist, perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), PFOA, perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) induced proliferation of human endometrial cancer cell Ishikawa at human exposure-related concentrations by binding and activating ERRγ. In vivo, PFHxA, PFOA and PFDA induced ovarian damage in zebrafish at 3.2 μM, 2.4 μM and 1.9 μM, respectively. PFCAs also induced sex hormones disturbance and interfered with sex hormone synthesis- and ERRγ pathway-related gene expression. In particular, PFOA exhibited estrogen-disturbing effects at the environmentally relevant concentration. Maternal exposure to PFCAs produced abnormal development of zebrafish offspring by disturbing the sex hormones and ERRγ pathway-related gene expression. All the effects were mitigated by an ERRγ antagonist. In conclusion, PFCAs could cause estrogen-disrupting effects and transgenerational effects through the ERRγ pathway. The study revealed a novel insight into the estrogen-disrupting effects of PFCAs.

Keywords: Co-exposure; Estrogen-disrupting effects; Estrogen-related receptor γ; Perfluorocarboxylic acids; Transgenerational effects.