Cadmium induced mouse spermatogonia apoptosis via mitochondrial calcium overload mediated by IP3R-MCU signal pathway

Abstract

Cadmium (Cd) is a toxic metal and also a well-known reproductive toxicant. Cd could induce germ cells apoptosis in mouse testes, however, the mechanism remains unclear. This study designed in vitro using GC-1 spermatogonial (spg) cells to explore the cytotoxicity and the molecular mechanisms induced by cadmium chloride(CdCl₂). As expected, CdCl₂ elevated the levels of reactive oxygen species (ROS) and induced the release of AIF and Cyt-c from the mitochondria to the cytosol in spermatogonia. Correspondingly, CdCl₂ apparently increased the apoptotic rate in spermatogonia. Further researches found that CdCl₂ could activate IP₃R-MCU pathway, trigger Ca²⁺ transfer from endoplasmic reticulum to mitochondria, and cause mitochondrial Ca²⁺ overload. BAPTA acetoxymethyl ester (BAPTA-AM), a calcium chelator, almost completely attenuated IP₃R phosphorylation, inhibited the mRNA and protein expression levels of VDAC1, MCU and MCUR1 upregulated by CdCl₂, reduced the calcium ion content in the mitochondria. Moreover, BAPTA-AM could decrease the level of ROS, antagonize CdCl₂-induced release of AIF and Cyt-c from the mitochondria to the cytosol and alleviate CdCl₂-induced apoptosis in spermatogonia. As above, these results provided the evidence that CdCl₂ might induce apoptosis of spermatogonia via mitochondrial Ca²⁺ overload mediated by IP₃R-MCU signal pathway.

Keywords: Apoptosis; Environmental cadmium; IP(3)R; MCU; Mitochondrial Ca(2+) overload; Spermatogonia.