SIRT1/PGC-1α is involved in arsenic-induced male reproductive damage through mitochondrial dysfunction, which is blocked by the antioxidative effect of zinc. (1st March 2023)

• Record Type: Journal Article
• Authors: Ye, Fuping; Wu, Lu; Li, Han; Peng, Xiaoshan; Xu, Yuan; Li, Wenqi; Wei, Yongyue; Chen, Feng; Zhang, Jingshu; Liu, Qizhan
• Is Part Of: Environmental pollution. Volume 320(2023)
• Publication Date: 2023-03-01
• Subjects: Arsenic -- Zinc -- Male reproductive damage -- Oxidative stress -- Mitochondrial dysfunction; Pollution -- Periodicals; Pollution -- Environmental aspects -- Periodicals; Environmental Pollution -- Periodicals; Pollution -- Périodiques; Pollution -- Aspect de l'environnement -- Périodiques; Pollution -- Effets physiologiques -- Périodiques; Pollution; Pollution -- Environmental aspects; Periodicals; Electronic journals; 363.73
• DOI: 10.1016/j.envpol.2023.121084
• Languages: English
• ISSNs: 0269-7491

Abstract

Abstract: Exposure to arsenic poses threats to male reproductive system, including impairing the testes and sperm quality. Although an association regarding arsenic exposure and male reproductive damage has been reported, the undergoing molecular mechanisms and interventions for prevention remain unclear. For the present work, male mice were exposed to 0, 2.5, 5, or 10 ppm sodium arsenite (NaAsO2 ) for 8 months. The results showed that arsenic-exposed mice had reduced fertility with abnormalities in the testes, epididymides, and sperm. Exposure of mice to arsenic caused a redox imbalance, decreased SIRT1 and PGC-1α levels, and affected mitochondrial biogenesis and proteins related to mitochondrial dynamics. For immortalized spermatogenic (GC-2) cells, arsenic caused apoptosis and oxidative stress, reduced SIRT1/PGC-1α levels and ATP production, inhibited mitochondrial respiration, and changed the mitochondrial membrane potential (MMP). Mitochondrial biogenesis and dynamics were also impaired. However, by reducing mitochondrial damage in GC-2 cells, upregulation of SIRT1 or zinc (Zn) supplementation reversed the apoptosis induced by arsenic. For mice, Zn supplementation blocked arsenic-induced oxidative stress, the decreases of SIRT1 and PGC-1α levels, and the impairment of mitochondrial function, and it reversed the damage to testes, low sperm quality, and low litter size. Collectively, these results suggest that arsenic causes excessive production of ROS, inhibits the SIRT1/PGC-1α pathway, and causing mitochondrial dysfunction by mediating impairment of mitochondrial biogenesis and dynamics, which results in germ cells apoptosis and male reproductive damage, processes that are blocked by Zn via an antioxidative effect. Our study contributes to understanding of the mechanisms for arsenic-induced male reproductive damage and points to the therapeutic significance of Zn. Graphical abstract: A mechanism for arsenic-induced male reproductive damage through oxidative stress and mitochondrial dysfunction, which is blocked by zinc (Zn) via an antioxidative effect. Arsenic exposure elevates the levels of ROS, inhibiting the NRF1/TFAM pathway through SIRT1/PGC-1α, and then induces impairment of mitochondrial biogenesis and dynamics, causing mitochondrial dysfunction and resulting in germ cells apoptosis and low sperm quality, which are associated with male reproductive damage. Zn prevents these arsenic-induced effects. Image 1 Highlights: Arsenic induces germ cells apoptosis and low sperm quality by oxidative stress. Arsenic impairs mitochondrial function by inhibiting SIRT1/PGC-1α. Inhibition of SIRT1/PGC-1α is involved in arsenic-induced male reproductive damage. Zinc blocks arsenic-induced male reproductive damage via reducing oxidative damage.