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Asian Journal of Andrology (2013) 15, 290–296; doi:10.1038/aja.2012.129; published online 28 January 2013
N-acetylcysteine protects against cadmium-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in testes
Yan-Li Ji*, Hua Wang*, Cheng Zhang, Ying Zhang, Mei Zhao, Yuan-Hua Chen and De-Xiang Xu
Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China
Correspondence: Professor DX Xu, (xudex@126.com)
* These authors contributed equally to this work.
Received 27 May 2012; Revised 10 August 2012; Accepted 31 August 2012
Advance online publication 28 January 2013
| Abstract |
Cadmium (Cd) is a reproductive toxicant that induces germ cell apoptosis in the testes. Previous studies have demonstrated that endoplasmic reticulum (ER) stress is involved in Cd-induced germ cell apoptosis. The aim of the present study was to investigate the effects of N-acetylcysteine (NAC), an antioxidant, on Cd-induced ER stress and germ cell apoptosis in the testes. Male CD-1 mice were intraperitoneally injected with CdCl2 (2.0 mg kg−1). As expected, acute Cd exposure induced germ cell apoptosis in the testes, as determined by terminal dUTP nick-end labelling (TUNEL). However, the administration of NAC alleviated Cd-induced germ cell apoptosis in the testes. Further analysis showed that NAC attenuated the Cd-induced upregulation of testicular glucose-regulated protein 78 (GRP78), an important ER molecular chaperone. Moreover, NAC inhibited the Cd-induced phosphorylation of testicular eukaryotic translation initiation factor 2α (eIF2α), a downstream target of the double-stranded RNA-activated kinase-like ER kinase (PERK) pathway. In addition, NAC blocked the Cd-induced activation of testicular X binding protein (XBP)-1, indicating that NAC attenuates the Cd-induced ER stress and the unfolded protein response (UPR). Interestingly, NAC almost completely prevented the Cd-induced elevation of C/EBP homologous protein (CHOP) and phosphorylation of c-Jun N-terminal kinase (JNK), two components of the ER stress-mediated apoptotic pathway. In conclusion, NAC protects against Cd-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in the testes.
Keywords: antioxidant; apoptosis; cadmium; endoplasmic reticulum stress; N-acetylcysteine (NAC); testis; unfolded protein response |
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