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  2. 1-Nitropyrene disrupts testicular steroidogenesis via oxidative stress-evoked PERK-eIF2α pathway

1-Nitropyrene disrupts testicular steroidogenesis via oxidative stress-evoked PERK-eIF2α pathway

  • Ecotoxicol Environ Saf. 2023 May 17;259:115027. doi: 10.1016/j.ecoenv.2023.115027.
Xiu-Liang Li 1 Yu-Lin Liu 1 Jia-Yu Liu 1 Yan-Yan Zhu 1 Xin-Xin Zhu 1 Wei-Wei Zhang 1 Jian Li 1 Ye Zhao 2 Ling-Li Zhao 1 Cheng Zhang 1 Hua Wang 1 De-Xiang Xu 3 Lan Gao 4
Affiliations

Affiliations

  • 1 Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes & Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, 230032, China.
  • 2 Department of Nuclear Medicine, Anhui Medical University, Hefei 230032, China.
  • 3 Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes & Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, 230032, China. Electronic address: xudex@126.com.
  • 4 Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes & Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, 230032, China. Electronic address: gaolan@ahmu.edu.cn.
Abstract

Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.

Keywords

1-NP; Antioxidant; ER stress; PERK-eIF2α; Testosterone.

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