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  2. Endoplasmic reticulum stress promotes blood-testis barrier impairment in mice with busulfan-induced oligospermia through PERK-eIF2α signaling pathway

Endoplasmic reticulum stress promotes blood-testis barrier impairment in mice with busulfan-induced oligospermia through PERK-eIF2α signaling pathway

  • Toxicology. 2022 May 15;473:153193. doi: 10.1016/j.tox.2022.153193.
Jianan Zhao 1 Minxin Wang 1 Yanan Wang 2 Jinyu Xu 1 Chenxu Ma 2 Yu Tang 1 QianQian Luo 1 Hongqin Zhang 3 Feibo Xu 4
Affiliations

Affiliations

  • 1 Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai 264003, PR China; Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai 264003, PR China.
  • 2 Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai 264003, PR China.
  • 3 Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai 264003, PR China; Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai 264003, PR China. Electronic address: byzhhq@163.com.
  • 4 Department of Histology and Embryology, College of Basic Medicine, Binzhou Medical University, Yantai 264003, PR China; Xu Rongxiang Regenerative Medicine Research Center, Binzhou Medical University, Yantai 264003, PR China. Electronic address: feiboxu@126.com.
Abstract

Busulfan, a chemotherapeutic agent for Cancer, has detrimental effects on germ cells and fertility, yet the specific mechanisms remain largely uncertain. The blood-testis barrier (BTB) maintains a suitable microenvironment for germ cells self-renewal and spermatogenesis by blocking the interference and damage of deleterious substances. Therefore, we hypothesized that BTB abnormalities might be involved in busulfan-induced oligospermia. To verify the hypothesis, thirty male Balb/c mice were randomly administered with busulfan (at a total dose of 40 mg/kg body weight) by intraperitoneal injection for 4 weeks to establish the model of oligospermia. The results displayed that busulfan caused testicular histopathological lesions and spermatogenesis disorder. Meanwhile, busulfan disrupted BTB integrity and lessened the expressions of BTB junction proteins, including Occludin, Claudin-11 and Connexin-43. Furthermore, busulfan activated the endoplasmic reticulum (ER) stress and PERK-eIF2α signaling pathway, reflected by the increased protein expressions of GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. Finally, to evaluate whether the ER stress is involved in busulfan-induced BTB destruction, the ER stress inhibitor 4-Phenylbutyric acid (4-PBA, 1 mM) was used to intervene in busulfan-exposed TM4 cells. The results displayed that inhibition of ER stress alleviated the reduction of BTB junction protein expressions induced by busulfan in TM4 cells. These data collectively indicated that busulfan-induced BTB impairment was mediated by triggering ER stress and activation of the PERK-eIF2α signaling pathway, thereby damaging the spermatogenesis, providing a new therapeutic target for male infertility induced by busulfan.

Keywords

BTB; Busulfan; ER stress; Oligospermia; PERK-eIF2α signaling pathway.

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