Loss of Atg5 in Sertoli cells enhances the susceptibility of cadmium-impaired testicular spermatogenesis in mice

Authors：Yong-Wei Xiong , Dai-Xin Li , Zheng-Jia Ling , Lu-Lu Tan , Yu-Feng Zhang , Jin Zhang , Hao Li , Wei Chang , Hua-Long Zhu , Jun Zhang , Lan Gao , De-Xiang Xu , Lan Yang , Hua Wang

Source：Food Chem Toxicol. 2023 Jul 26;179:113967.

DOI: 10.1016/j.fct.2023.113967

Abstract：

Cadmium (Cd), one of the most common contaminants in diet and drinking water, impairs testicular germ cell development and spermatogenesis. Autophagy is essential for maintaining Sertoli cell function and Sertoli-germ cell communication. However, the role of Sertoli cell autophagy in Cd-caused spermatogenesis disorder remains unclear. Here, the mice of autophagy-related gene 5 (Atg5) knockouts in Sertoli cells were used to investigate the effect of autophagy deficiency on Cd-impaired spermatogenesis and its underlying mechanisms. Results showed that Sertoli cell-specific knockout of Atg5 exacerbated Cd-reduced sperm count and MVH (a specific marker for testicular germ cells) level in mice. Additionally, Sertoli cell Atg5 deficiency reduced the number of spermatocytes and decreased the level of meiosis-related proteins (SYCP3 and STRA8) in Cd-treated mouse testes. Loss of Atg5 in Sertoli cell exacerbated Cd-reduced the level of retinoic acid (RA) and retinal dehydrogenase (ALDH1A1 and ALDH1A) in mouse testes. Meanwhile, we found that the level of transcription factor WT1 was significantly downregulated in Atg5-/-plus Cd-treated testes. Further experiments showed that Wt1 overexpression restored Cd-decreased the levels of ALDH1A1 in Sertoli cells. Collectively, the above data suggest that knockout of Atg5 in Sertoli cell enhances the susceptibility of Cd-impaired testicular spermatogenesis. These findings provide new insights into autophagy of Sertoli cell preventing environmental toxicants-impaired testicular spermatogenesis.

摘要：

镉（Cd）是饮食和饮用水中最常见的污染物之一，会损害睾丸生殖细胞的发育和精子生成。自噬是维持凋亡细胞功能和凋亡细胞与生殖细胞交流的必要条件。然而，Sertoli细胞自噬在镉引起的精子发生障碍中的作用仍不清楚。在此，研究人员利用敲除Sertoli细胞中自噬相关基因5（Atg5）的小鼠来研究自噬缺陷对镉致精子发生障碍的影响及其内在机制。结果表明，特异性敲除 Sertoli 细胞的 Atg5 会加剧 Cd 对小鼠精子数量和 MVH（睾丸生殖细胞的特异性标记物）水平的影响。此外，在镉处理过的小鼠睾丸中，Sertoli细胞Atg5缺乏会减少精母细胞的数量，并降低减数分裂相关蛋白（SYCP3和STRA8）的水平。Sertoli细胞中Atg5的缺失加剧了镉对小鼠睾丸视黄酸（RA）和视黄醛脱氢酶（ALDH1A1和ALDH1A）水平的降低。与此同时，我们发现在Atg5-/加Cd处理的睾丸中，转录因子WT1的水平显著下调。进一步的实验表明，Wt1的过表达可恢复Sertoli细胞中因Cd而降低的ALDH1A1水平。总之，上述数据表明，在Sertoli细胞中敲除Atg5会增强镉损伤睾丸生精功能的易感性。这些发现提供了关于Sertoli细胞自噬防止环境毒物损害睾丸生精功能的新见解。