Journal
ENVIRONMENT INTERNATIONAL
Volume 167, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.envint.2022.107393
Keywords
GCN2/eIF2 alpha signaling; Ribosome stalling; Leydig cells; 1-NP; Reactive oxygen species; Testosterone synthesis
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Funding
- National Natural Science Foundation of China [91743105, 82003492]
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In this research, it was discovered that acute exposure to 1-nitropyrene (1-NP) from polluted atmosphere resulted in a decline in testosterone (T) level in men. The study found that the reduction of T contents was caused by the downregulation of steroidogenic proteins in mouse testes and Leydig cells. The mechanism involved the activation of GCN2 and mitochondrial ROS-mediated ribosome stalling, leading to the inhibition of steroidogenic activity.
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 eIF2 alpha 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 eIF2 alpha 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.
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