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  2. 1-Nitropyrene disrupts testosterone biogenesis via AKAP1 degradation promoted mitochondrial fission in mouse Leydig cell

1-Nitropyrene disrupts testosterone biogenesis via AKAP1 degradation promoted mitochondrial fission in mouse Leydig cell

  • Environ Pollut. 2022 Aug 15;307:119484. doi: 10.1016/j.envpol.2022.119484.
Wei-Wei Zhang 1 Xiu-Liang Li 1 Yu-Lin Liu 1 Jia-Yu Liu 1 Xin-Xin Zhu 1 Jian Li 1 Ling-Li Zhao 1 Cheng Zhang 1 Hua Wang 1 De-Xiang Xu 1 Lan Gao 2
Affiliations

Affiliations

  • 1 Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes & Department of Toxicology, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province, China.
  • 2 Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes & Department of Toxicology, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province, China. Electronic address: gaolan@ahmu.edu.cn.
Abstract

Previous study found 1-NP disrupted steroidogenesis in mouse testis, but the underlying mechanism remained elusive. The current work aims to explore the roles of ROS-promoted AKAP1 degradation and excessive mitochondrial fission in 1-NP-induced steroidogenesis disruption in MLTC-1 cells. Transmission electron microscope analysis found 1-NP promoted excessive mitochondrial fission. Further data showed 1-NP disrupted mitochondrial function. pDRP1 (Ser637), a negative regulator of mitochondrial fission, was reduced in 1-NP-treated MLTC-1 cells. Mechanistically, 1-NP caused degradation of AKAP1, an upstream regulator of pDRP1 (Ser637). MG132, a Proteasome Inhibitor, attenuated 1-NP-induced AKAP1 degradation and downstream pDRP1 (Ser637) reduction, thereby ameliorating 1-NP-downregulated steroidogenesis. Further analysis found that cellular ROS was elevated and NOX4, HO-1 and SOD2 were upregulated in 1-NP-exposed MLTC-1 cells. NAC, a well-known commercial antioxidant, alleviated 1-NP-induced excessive ROS and oxidative stress. 1-NP-induced AKAP1 degradation and subsequent downregulation of pDRP1 (Ser637) were prevented by NAC pretreatment. Moreover, NAC attenuated 1-NP-resulted T synthesis disturbance in MLTC-1 cells. The present study indicates that ROS mediated AKAP1 degradation and subsequent pDRP1 (Ser637) dependent mitochondrial fission is indispensable in 1-NP caused T synthesis disruption. This study provides a new insight into 1-NP-induced endocrine disruption, and offers theoretical basis in public health prevention.

Keywords

1-Nitropyrene; AKAP1; MLTC-1 cell; Mitochondrial fission; ROS; T synthesis.

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