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Nickel sulfate induced apoptosis via activating ROS-dependent mitochondria and endoplasmic reticulum stress pathways
Lingyue Zou1, Li Su1, Yifan Sun1
1Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China.
Abstract:
Nickel can induce apoptosis of testicular Leydig cells in mice, whereas the mechanisms remain unclear. In this study, we investigated the role of nickel-induced reactive oxygen species (ROS) generation in mitochondria and endoplasmic reticulum stress (ERS) mediated apoptosis pathways in rat Leydig cells. Fluorescent DCF and Annexin-V FITC/PI staining were performed to measure the production of ROS and apoptosis in Leydig cells. RT-qPCR and Western blot were conducted to analyze the key genes and proteins involved in mitochondria and ERS apoptotic pathways. The results showed that nickel sulfate induced ROS generation, consequently resulted in nucleolus deformation and apoptosis in testicular Leydig cells, which were then attenuated by ROS inhibitors of N-acetylcysteine (NAC) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). Nickel sulfate-triggered Leydig cells apoptosis via mitochondria and ERS pathways was characterized by the upregulated mRNA and proteins expression of Bak, cytochrome c, caspase 9, caspase 3, GRP78, GADD153, and caspase 12, which were inhibited by NAC and TEMPO respectively. The findings indicated that nickel-induced ROS generation was involved in apoptosis via mitochondria and ERS pathways in rat Leydig cells.
Insights
Nickel exposure triggers reactive oxygen species (ROS) generation, leading to testicular Leydig cell apoptosis via mitochondrial and endoplasmic reticulum stress pathways. ROS inhibitors like NAC and TEMPO mitigate these nickel-induced effects.
Area of Science:
- Toxicology
- Cell Biology
- Reproductive Biology
Background:
- Nickel exposure is a known toxicant.
- The precise mechanisms of nickel-induced testicular Leydig cell apoptosis are not fully understood.
- Reactive oxygen species (ROS) and endoplasmic reticulum stress (ERS) are implicated in cellular damage.
Purpose of the Study:
- To investigate the role of nickel-induced ROS generation in mitochondria and ERS-mediated apoptosis in rat Leydig cells.
- To elucidate the specific molecular pathways involved in nickel-induced Leydig cell death.
Main Methods:
- Leydig cells were exposed to nickel sulfate.
- ROS production was measured using fluorescent DCF staining.
- Apoptosis was assessed via Annexin-V FITC/PI staining.
- Gene and protein expression related to mitochondrial and ERS apoptotic pathways were analyzed using RT-qPCR and Western blot.
Main Results:
- Nickel sulfate induced significant ROS generation and nucleolus deformation in Leydig cells.
- Nickel sulfate triggered apoptosis, evidenced by changes in apoptotic markers.
- ROS inhibitors N-acetylcysteine (NAC) and TEMPO attenuated nickel-induced ROS and apoptosis.
- Nickel sulfate upregulated key genes and proteins in mitochondrial (Bak, cytochrome c, caspase 9, caspase 3) and ERS (GRP78, GADD153, caspase 12) apoptotic pathways, which were reversed by NAC and TEMPO.
Conclusions:
- Nickel-induced ROS generation plays a critical role in the apoptosis of rat Leydig cells.
- Mitochondrial and endoplasmic reticulum stress pathways are key mediators of nickel-induced Leydig cell apoptosis.
- ROS inhibition offers a potential protective strategy against nickel toxicity in testicular cells.
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