Cadmium induces autophagy via IRE1 signaling pathway activated by Ca^2 + in GC-2spd cells

Area of Science:

• Toxicology
• Reproductive Biology
• Cellular Stress Response

Background:

• Cadmium (Cd) is an environmental toxicant known to accumulate in the body and cause male reproductive damage.
• The precise molecular mechanisms of Cd-induced reproductive toxicity remain incompletely understood.
• Endoplasmic reticulum stress (ERS) and autophagy are implicated in cellular toxicity.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying Cadmium-induced male reproductive toxicity.
• To investigate the roles of calcium homeostasis, endoplasmic reticulum stress (ERS), and autophagy in Cadmium toxicity.
• To evaluate the therapeutic potential of IP3R and IRE1 inhibitors against Cadmium-induced damage.

Main Methods:

• GC-2spd cells were treated with Cadmium chloride (CdCl2).
• Inhibitors of inositol trisphosphate receptor (IP3R) (2-APB) and Endoplasmic Reticulum (ER) stress effector protein IRE1 (STF-083010) were used.
• Techniques included confocal microscopy, flow cytometry, and MDC assay to assess calcium homeostasis, ER stress markers, and autophagy.

Main Results:

• CdCl2 treatment induced calcium imbalance and upregulated IP3R and IRE1 expression in GC-2spd cells, indicating activation of ERS.
• Cd exposure increased autophagosome formation and expression of autophagy-related proteins (LC3-II/LC3-I, Beclin-1).
• Treatment with 2-APB and STF-083010 inhibited autophagy, mitigated cell death, restored calcium homeostasis, and reduced ERS.

Conclusions:

• Cadmium-induced male reproductive toxicity is mediated by disruption of calcium homeostasis, leading to IRE1 pathway-activated ERS and excessive autophagy.
• Inhibiting IP3R and IRE1 offers a synergistic protective effect by restoring calcium and ER homeostasis, thereby reducing autophagy and cell death.
• Targeting calcium imbalance and ERS presents a promising therapeutic strategy for Cadmium-induced male reproductive disorders.