Cadmium exposure during puberty damages testicular development and spermatogenesis via ferroptosis caused by intracellular iron overload and oxidative stress in mice. (15th May 2023)

• Record Type: Journal Article
• Authors: Wang, Yi; Wu, Jie; Zhang, Mingming; OuYang, Huijuan; Li, Mengyuan; Jia, Didi; Wang, Rong; Zhou, Weiyi; Liu, Hao; Hu, Yuan; Yao, Yuyou; Liu, Yehao; Ji, YanLi
• Is Part Of: Environmental pollution. Volume 325(2023)
• Publication Date: 2023-05-15
• Subjects: Cadmium -- Ferroptosis -- Iron overload -- Oxidative stress -- Testis -- Spermatogenesis; 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.2023.121434
• Languages: English
• ISSNs: 0269-7491

Abstract

Abstract: Cadmium (Cd) is a widespread environmental pollutant and a reproductive toxicant. It has been proved that Cd can reduce male fertility, however, the molecular mechanisms remain unveiled. This study aims to explore the effects and mechanisms of pubertal Cd exposure on testicular development and spermatogenesis. The results showed that Cd exposure during puberty could cause pathological damage to testes and reduce sperm counts in mice in adulthood. Moreover, Cd exposure during puberty reduced GSH content, induced iron overload and ROS production in testes, suggesting that Cd exposure during puberty may induce testicular ferroptosis. The results in vitro experiments further strengthened that Cd caused iron overload and oxidative stress, and decreased MMP in GC-1 spg cells. In addition, Cd disturbed intracellular iron homeostasis and peroxidation signal pathway based on transcriptomics analysis. Interestingly, these changes induced by Cd could be partially suppressed by pretreated with ferroptotic inhibitors, Ferrostatin-1 and Deferoxamine mesylate. In conclusion, the study demonstrated that Cd exposure during puberty maybe disrupted intracellular iron metabolism and peroxidation signal pathway, triggered ferroptosis in spermatogonia, and ultimately damaged testicular development and spermatogenesis in mice in adulthood. Graphical abstract: Cd regulates the expression of TFR1, FTH1 and FPN1, key genes of the iron regulatory network, causing iron overload in spermatogonia. In addition, Cd decreases GSH levels. Excessive iron and GSH depletion trigger lipid peroxidation by producing ROS and eventually cause ferroptosis in spermatogonia, which at least partially, contribute to testicular development and spermatogenesis injury in mice exposed to Cd during puberty. Image 1 Highlights: Cd exposure during puberty damages testicular development and spermatogenesis. Cd exposure during puberty induces testicular ferroptosis. Cd induces oxidative stress in GC-1 spg cells. Cd induces intracellular iron overload and oxidative stress, triggers ferroptosis in GC-1 spg cells.