2. Academic Validation
  3. Disruption of zebrafish sex differentiation by emerging contaminants hexafluoropropylene oxides at environmental concentrations via antagonizing androgen receptor pathways

Disruption of zebrafish sex differentiation by emerging contaminants hexafluoropropylene oxides at environmental concentrations via antagonizing androgen receptor pathways

  • Environ Int. 2024 Jul 2:190:108868. doi: 10.1016/j.envint.2024.108868.
Tingyu Lu 1,  Wei Zheng 1,  Fanglin Hu 1,  Xicha Lin 1,  Ran Tao 1,  Minjie Li 2,  Liang-Hong Guo 3
Affiliations

Affiliations

  • 1 College of Life Science, China Jiliang University, Hangzhou, Zhejiang 310018, China; Institute of Environmental and Health Sciences, China Jiliang University, Hangzhou, Zhejiang 310018, China.
  • 2 Institute of Environmental and Health Sciences, China Jiliang University, Hangzhou, Zhejiang 310018, China; College of Quality and Safety Engineering, China Jiliang University, Hangzhou, Zhejiang 310018, China. Electronic address: mjli@cjlu.edu.cn.
  • 3 Institute of Environmental and Health Sciences, China Jiliang University, Hangzhou, Zhejiang 310018, China; College of Quality and Safety Engineering, China Jiliang University, Hangzhou, Zhejiang 310018, China. Electronic address: lhguo@cjlu.edu.cn.
PMID: 38976939 DOI: 10.1016/j.envint.2024.108868
Abstract

As alternatives of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimeric acid (HFPO-DA) and trimeric acid (HFPO-TA) have been detected increasingly in environmental media and even humans. They have been shown to exhibit reproductive toxicity to model species, but their effects on human remain unclear due to the knowledge gap in their mode of action. Herein, (anti-)androgenic effects of the two HFPOs and PFOA were investigated and underlying toxicological mechanism was explored by combining zebrafish test, cell assay and molecular docking simulation. Exposure of juvenile zebrafish to the chemicals during sex differentiation promoted feminization, with HFPO-TA acting at an environmental concentration of 1 μg/L. The chemicals inhibited proliferation of human prostate cells and transcriptional activity of human and zebrafish androgen receptors (AR), with HFPO-TA displaying the strongest potency. Molecular docking revealed that the chemicals bind to AR in a conformation similar to a known AR antagonist. Combined in vivo, in vitro and in silico results demonstrated that the chemicals disrupted sex differentiation likely by antagonizing AR-mediated pathways, and provided more evidence that HFPO-TA is not a safe alternative to PFOA.

Keywords

Androgen receptor; Antagonist; Hexafluoropropylene oxide; Perfluorooctanoic acid; Sex differentiation; Zebrafish.

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