Cadmium-induced apoptosis of Leydig cells is mediated by excessive mitochondrial fission and inhibition of mitophagy

Abstract

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.

Aflatoxin B1-Induced Testosterone Biosynthesis Disorder via the ROS/AMPK Signaling Pathway in Male Mice

“…The reduction in the T, LH, and FSH hormone levels was also found in other studies exposed to AFB 1 . , Undoubtedly, the numbers and function of LCs directly affect T production . 3β-HSD is the biomarker of the LCs lineage . From the immunohistochemical results in our study, AFB 1 reduced 3β-HSD-positive cells, indicating AFB 1 caused a decrease in the number of LCs in mice testis.…”

“…13 3β-HSD is the biomarker of the LCs lineage. 37 From the immunohistochemical results in our study, AFB 1 reduced 3β-HSD-positive cells, indicating AFB 1 caused a decrease in the number of LCs in mice testis. Consistently, our results also showed that AFB 1 exhibited cytotoxicity on TM3 cells, evidenced by the disrupted cellular ultrastructure and decreased cell viability and density.…”

Involvement of ERK and Oxidative Stress in Airway Exposure to Cadmium Chloride Aggravates Airway Inflammation in Ovalbumin-Induced Asthmatic Mice

“…The primary routes of human exposure are inhalation and ingestion, leading to the accumulation of Cd in vital organs [ 5 , 6 ], including the kidneys, lungs, and intestines [ 7 ]. Exposure to Cd can result in various types of systemic damage, including liver and kidney dysfunction, pulmonary edema, and reproductive toxicity [ 4 , 8 , 9 ]. Moreover, Cd has been identified as a carcinogen, with occupational or environmental exposure being associated with lung, breast, bladder, and other types of cancers [ 10 , 11 , 12 ].…”

Associations of Sperm Mitochondrial DNA Copy Number with Concentrations of Urinary Cadmium and Selenium

“…A higher Cd exposure may result in a higher sperm mtDNAcn through increasing oxidative stress. A study based on animal experiments reported that Cd exposure may decrease Leydig cells' function by increasing oxidative stress, which leads to an increase in mtDNAcn [29]. Another study reported prostate cancer patients' blood Cd was positively associated with blood mtDNAcn [30].…”