Mitochondrial ROS-mediated ribosome stalling and GCN2 activation are partially involved in 1-nitropyrene-induced steroidogenic inhibition in testes

  • Environ Int. 2022 Sep;167:107393. doi: 10.1016/j.envint.2022.107393.
Jian Li  1 ,  Lan Gao  2 ,  Jing Chen  1 ,  Wei-Wei Zhang  1 ,  Xiao-Yi Zhang  1 ,  Bo Wang  1 ,  Cheng Zhang  1 ,  Yan Wang  1 ,  Yi-Chao Huang  1 ,  Hua Wang  1 ,  Wei Wei  3 ,  De-Xiang Xu  4
Affiliations
  • 1. Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
  • 2. Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
  • 3. Key Laboratory of Anti-inflammatory & Immune Medicine, Education Ministry of China, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
  • 4. Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
PMID: 35843074 DOI: 10.1016/j.envint.2022.107393
Abstract

In the past 50 years, testosterone (T) level in men has declined gradually. In this research, we discovered that acute exposure to 1-nitropyrene (1-NP), an environmental stressor from polluted atmosphere, reduced T contents by downregulating steroidogenic proteins in mouse testes and Leydig cells. Acute 1-NP exposure caused GCN2 activation and eIF2α phosphorylation, a marker of integrated stress, in mouse testes and Leydig cells. GCN2iB, a selective GCN2 kinase inhibitor, and siGCN2, the GCN2-targeted short interfering RNA, attenuated 1-NP-induced reduction of steroidogenic proteins in Leydig cells. Mechanistically, mitochondrial membrane potential was reduced and ATP5A, UQCRC2, SDHB and NDUFB8, four OXPHOS subunits, were reduced in 1-NP-exposed Leydig cells. Cellular mitochondrial respiration was inhibited and ATP production was reduced. Moreover, mitochondrial Reactive Oxygen Species (ROS) were elevated in 1-NP-exposed Leydig cells. The interaction between GCN2 and uL10, a marker of ribosome stalling, was observed in 1-NP-exposed Leydig cells. MitoQ, a mitochondria-targeted antioxidant, attenuated1-NP-evoked ATP depletion and ribosome stalling in Leydig cells. Moreover, MitoQ suppressed 1-NP-caused GCN2 activation and eIF2α phosphorylation in Leydig cells. In addition, MitoQ alleviated 1-NP-induced steroidogenic inhibition in mouse testes. In conclusion, mitochondrial ROS-mediated ribosome stalling and GCN2 activation are partially involved in environmental stress-induced steroidogenic inhibition in testes.

Keywords
1-NP; GCN2/eIF2α signaling; Leydig cells; Reactive oxygen species; Ribosome stalling; Testosterone synthesis.
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