Cadmium induces apoptosis of mouse spermatocytes through JNK activation and disruption of autophagic flux

Lin Zhou; Yong Chen; Yu Sun; Nayu Li; Yunhao Liu; Wei Tan; Ling Zhang

doi:10.1016/j.ecoenv.2023.115505

Cadmium induces apoptosis of mouse spermatocytes through JNK activation and disruption of autophagic flux

Ecotoxicol Environ Saf. 2023 Oct 15:265:115505. doi: 10.1016/j.ecoenv.2023.115505. Epub 2023 Sep 22.

Authors

Lin Zhou¹, Yong Chen², Yu Sun¹, Nayu Li¹, Yunhao Liu¹, Wei Tan³, Ling Zhang⁴

Affiliations

¹ School of Public Health, Department of Environmental Health and Occupational Medicine, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan 430065, China.
² Emergency Department, Taikang Tongji (Wuhan) Hospital, Wuhan 430050, China.
³ Public Health Department, Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan 430065, China. Electronic address: tanwei@wust.edu.cn.
⁴ School of Public Health, Department of Environmental Health and Occupational Medicine, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan 430065, China. Electronic address: zhangling@wust.edu.cn.

PMID: 37742578
DOI: 10.1016/j.ecoenv.2023.115505

Abstract

Cadmium has been reported to accumulate primarily in spermatogonia and spermatocytes. Exposure to cadmium results in male reproductive toxicity via germ-cell apoptosis and impaired autophagy. Apoptosis and autophagy are two physiologically conserved events that maintain cellular homeostasis. However, the precise role of autophagy in cadmium-induced apoptosis of male germ cells has yet to be addressed. The present study aimed to investigate the impact of cadmium exposure on the cytotoxicity of GC-2 spd cells, a mouse spermatocyte cell line. The results showed that cadmium exposure caused apoptotic cell death and the accumulation of autophagosomes, along with the up-regulation of ATG proteins in GC-2 spd cells. It was demonstrated that the cadmium-induced accumulation of autophagosomes contributes to the apoptosis of GC-2 spd cells. This notion is supported by the findings that the autophagy inhibitor 3-MA reduced accumulation of autophagosomes and apoptotic cell death. Conversely, the apoptosis inhibitor Z-VAD-FMK inhibited apoptosis but had little effect on the accumulation of autophagosomes. Cadmium may impede the fusion of autophagosomes with lysosomes, leading to the autophagosome buildup. Additionally, we found that the JNK pathway mediates transcriptional induction of several autophagy-related (ATG) genes involved in autophagosome formation. The cadmium-activated JNK pathway regulates apoptosis by mediating the autophagosome formation. Treatment of cells with the JNK inhibitor SP600125 attenuated the accumulation of autophagosomes, the upregulated expression of autophagosome-associated proteins and apoptotic cell death induced by cadmium. Overall, these findings suggest that cadmium enhances apoptosis of GC-2 spd cells by activating the JNK pathway and inhibiting autophagic flux.

Keywords: Apoptosis; Autophagic flux; Cadmium; GC-2 spd cells; JNK.