ATF6 is a critical regulator of cadmium-mediated apoptosis in spermatocytes

In this study, we examined the mechanisms of cadmium exposure-induced endoplasmic reticulum (ER) stress response and apoptosis in spermatocytes. Responses to cadmium toxicity were investigated using spermatocytes overexpressing p50ATF6, ATF4, and spliced XBP1s, belonging to the 3 unfolded protein response pathways. The ER stress and apoptosis response to cadmium were most strongly stimulated through the activating transcription factor 6 (ATF6) pathway; in contrast, siRNA-induced inhibition of protein expression could reduce apoptosis under stressful conditions. An in vivo experiment using mice confirmed that upregulation of p50ATF6 in the testis increased apoptosis in response to cadmium exposure. Further, when confirming the correlation between ER stress and MAPK in cadmium toxicity, p38 MAPK phosphorylation was strongly regulated by p50ATF6; p-p38 also mediated the activity of p50ATF6. Overall, these findings suggest that modulating the activity of p38 MAPK and p50ATF6 in cadmium exposure-induced toxicity can be considered a potential strategy to treat infertility.

Automated summary

In this study, the mechanisms of cadmium exposure-induced endoplasmic reticulum (ER) stress response and apoptosis in spermatocytes were examined. The most significant response to cadmium toxicity was observed in the activating transcription factor 6 (ATF6) pathway. Inhibition of protein expression could reduce apoptosis under stressful conditions. Furthermore, p50ATF6 was found to regulate p38 MAPK phosphorylation, and p-p38 mediated the activity of p50ATF6, suggesting that modulating the activity of p38 MAPK and p50ATF6 can be a potential strategy to treat infertility caused by cadmium exposure.