Cadmium induces apoptosis of human granulosa cell line KGN via mitochondrial dysfunction-mediated pathways
Guofeng Xu1, Shuang Liu2, Mingquan Huang3
1Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
Abstract:
Cadmium (Cd) is an important industrial and environmental pollutant, which is closely correlated with female infertility. Although Cd-induced developmental disorders of human ovarian follicles have been widely reported, the underlying mechanisms remain not fully elucidated. In this study, we explored the mechanism underlying Cd-triggered apoptosis in granulosa cells. Following the treatment with various levels of Cd (0, 0.625, 1.25, 2.5 and 5 μM), we found that Cd triggered the death of KGN cells (a human granulosa-like tumor cell line) in a dose- as well as time-dependent manner. The levels of expressions of Bax and Bak were significantly increased, whereas the expression levels of Mcl-1 and Bcl-2 were considerably decreased after being treated with high levels of Cd. We showed that Cd exposure remarkably triggered mitochondrial dysfunction, including increased intracellular ROS and free Ca2+ levels, and decreased ATP generation and mitochondrial membrane potential. Furthermore, we found that mitochondrial dysfunction, especially excessive ROS production and intracellular Ca2+ overload, serve a vital role in Cd-triggered apoptosis of KGN cells. After using inhibitors to block the corresponding signaling cascades, Cd-mediated apoptosis was markedly repressed by ASK1 and p38 inhibitors in contrast with the control group. This suggests the activation of downstream pathways triggered by mitochondrial dysfunction participates in granulosa cell death and may cause female reproductive toxicity after Cd exposure.
Insights
Cadmium exposure triggers granulosa cell apoptosis by inducing mitochondrial dysfunction, increasing reactive oxygen species (ROS) and calcium overload. This cell death pathway, involving ASK1 and p38, contributes to female reproductive toxicity.
Area of Science:
- Environmental Toxicology
- Reproductive Biology
- Cellular Biology
Background:
- Cadmium (Cd) is an industrial pollutant linked to female infertility.
- Cd-induced ovarian follicle developmental disorders are known, but mechanisms are unclear.
- Granulosa cell apoptosis is a key factor in Cd-induced reproductive toxicity.
Purpose of the Study:
- To elucidate the mechanism of Cadmium-triggered apoptosis in human granulosa cells.
- To investigate the role of mitochondrial dysfunction in Cadmium-induced cell death.
- To identify key signaling pathways involved in Cadmium toxicity.
Main Methods:
- KGN cells were treated with varying Cadmium concentrations.
- Apoptosis, gene expression (Bax, Bak, Mcl-1, Bcl-2), mitochondrial function (ROS, Ca2+, ATP, membrane potential), and signaling pathways (ASK1, p38) were assessed.
- Inhibitors were used to block specific signaling cascades.
Main Results:
- Cadmium induced KGN cell death in a dose- and time-dependent manner.
- Cadmium exposure increased pro-apoptotic proteins (Bax, Bak) and decreased anti-apoptotic proteins (Mcl-1, Bcl-2).
- Cadmium triggered mitochondrial dysfunction, including increased ROS and Ca2+ overload, and decreased ATP and mitochondrial membrane potential.
- ASK1 and p38 pathway inhibitors significantly repressed Cadmium-mediated apoptosis.
Conclusions:
- Mitochondrial dysfunction, particularly ROS and Ca2+ overload, is crucial in Cadmium-induced granulosa cell apoptosis.
- The ASK1-p38 signaling pathway is activated downstream of mitochondrial dysfunction, contributing to Cadmium-induced granulosa cell death.
- These findings highlight a mechanism for Cadmium's reproductive toxicity in females.
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