Cadmium is one of the environmental and occupational pollutants and its potential adverse effects on human health have given rise to substantial concern. Cadmium causes damage to the male reproductive system via induction of germ-cell apoptosis; however, the underlying mechanism of cadmium-induced reproductive toxicity in Leydig cells remains unclear. In this study, twenty mice were divided randomly into four groups and exposed to CdCl2 at concentrations of 0, 0.5, 1.0 and 2.0 mg/kg/day for four consecutive weeks. Testicular injury, abnormal spermatogenesis and apoptosis of Leydig cells were observed in mice. In order to investigate the mechanism of cadmium-induced apoptosis of Leydig cells, a model of mouse Leydig cell line (i.e. TM3 cells) was subjected to treatment with various concentrations of CdCl2. It was found that mitochondrial function was disrupted by cadmium, which also caused a significant elevation in levels of mitochondrial superoxide and cellular ROS. Furthermore, while cadmium increased the expression of mitochondrial fission proteins (DRP1 and FIS1), it reduced the expression of mitochondrial fusion proteins (OPA1 and MFN1). This led to excessive mitochondrial fission, the release of cytochrome c and apoptosis. Conversely, cadmium-induced accumulation of mitochondrial superoxide was decreased by the inhibition of mitochondrial fission through the use of Mdivi-1 (an inhibitor of DRP1). Mdivi-1 also partially prevented the release of cytochrome c from mitochondria to cytosol and attenuated cell apoptosis. Finally, given the accumulation of LC3II and SQSTM1/p62 and the obstruction of Parkin recruitment into damaged mitochondria in TM3 cells, the autophagosome-lysosome fusion was probably inhibited by cadmium. Overall, these findings suggest that cadmium induces apoptosis of mouse Leydig cells via the induction of excessive mitochondrial fission and inhibition of mitophagy.
Di(2-ethylhexyl)phthalate (DEHP) is a typical endocrine-disrupting chemical and reproductive toxicant. Although previous studies have attempted to describe the mechanism by which DEHP exposure results in reproductive dysfunction, few studies focused on puberty, a critical period of reproductive development, and the increased susceptibility to injury in adolescents. To elucidate the mechanism underpinning the testicular effects of DEHP in puberty, we sought to investigate the JAZF1/TR4 pathway in the testes of pubertal rats. Specifically, we focused on the role of the JAZF1/TR4 pathway in male reproduction, including the genes JAZF1, TR4, Sperm 1, and Cyclin A1. In the present study, rats were exposed to increasing concentrations of DEHP (0, 250, 500, and 1000 mg/kg/day) by oral gavages for 30 days. Then we assayed testicular zinc and oxidative stress levels. Our results indicated that DEHP exposure could lead to oxidative stress and decrease the contents of testicular zinc. Additionally, significant morphological changes and cell apoptosis were observed in testes exposed to DEHP, as identified by hematoxylin and eosin staining and the terminal deoxynucleotidyl transferase-mediated nick and labeling assay. By measuring the expression levels of the above relevant genes by qPCR, we found the DEHP-induced increased expression of JAZF1 and decreased expression of TR4, Sperm 1, and Cyclin A1. Therefore, we have demonstrated that in vivo exposure to DEHP might induce reproductive toxicity in pubertal male rats through the JAZF1/TR4 pathway and oxidative stress.
Cadmium (Cd) is a heavy metal that is widely present in modern industrial production. It is a known, highly toxic environmental endocrine disruptor. Long-term exposure to Cd can cause varying degrees of damage to the liver, kidney, and reproductive system of organisms, especially the male reproductive system. This study aimed to explore the mechanism of Cd toxicity in the male reproductive system during puberty. Eighteen healthy 6-week-old male Sprague–Dawley rats were randomly divided into three groups (control group, low-dose group, and high-dose group) according to their body weight, with six in each group. Cd (0, 1, and 3 mg/kg/day) was given by gavage for 28 consecutive days. The results showed that Cd exposure to each dose group caused a decrease in the testicular organ coefficient and sperm count, compared with the control group. Cd exposure resulted in significant changes in testicular morphology in the 3 mg/kg/day Cd group. In the 1 and 3 mg/kg/day Cd groups, serum testosterone decreased and apoptosis of testicular cells increased significantly ( p < 0.05). In addition, compared with the control group, the activity of glutathione peroxidase and superoxide dismutase in each Cd exposure dose group decreased, but the content of malondialdehyde in the high-dose, 3 mg/kg/day Cd treatment group significantly increased ( p < 0.05). Although Cd exposure caused an increase in the messenger RNA (mRNA) levels of Bcl-2, Caspase-3 and Caspase-9 in the testicular tissues ( p < 0.05), Bcl-2 expression was unchanged ( p > 0.05). The expression level of Akt mRNA in testicular tissue of rats in the high-dose 3 mg/kg/day Cd group was increased ( p < 0.05). Our data suggest that Cd affected testosterone levels, and apoptosis was observed in spermatids.
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