Yang Si, Yang Ying, Xu Linlin, Hao Chaoju, Chen Jiaxiang
Department of Physiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, P. R. China.
Huankui Academy, Jiangxi Medical College, Nanchang University, Nanchang, 330006, P. R. China.
Adv Sci (Weinh). 2025 May;12(17):e2413936. doi: 10.1002/advs.202413936. Epub 2025 Mar 6.
Dibutyl phthalate (DBP) has been widely used in the manufacture of various daily and industrial products. As one of the most important endocrine disruptors, DBP has male reproductive toxicity and can lead to testicular dysfunction. In view of the fact that Leydig cells are important functional and structural units in the testis, their damage will affect testicular function. However, the underlying mechanism of DBP-caused damage to mouse Leydig cells remains elusive. In the study, it is confirmed that DBP can promote the expression of death-associated protein kinase 3 (DAPK3), thereby inducing autophagy of mouse Leydig cells by using in vivo and in vitro experiments. Also, bioinformatics analysis and molecular biology experimental techniques are utilized to further demonstrate that DBP-induced upregulation of DAPK3 results from both the activated transcription by specific protein 2 (Sp2) and the decreased ubiquitination and degradation by parkin RBR E3 ubiquitin-protein ligase (PRKN). Interestingly, melatonin can inhibit both Sp2/DAPK3 and PRKN/DAPK3 signaling pathways by inhibiting oxidative stress, thereby alleviating DBP-induced autophagy of mouse Leydig cells. Overall, the study unravels a novel regulatory mechanism of DBP-induced autophagy of mouse Leydig cells and identifies DAPK3 as a potential therapeutic target for DBP-caused damage to the male reproductive system.
邻苯二甲酸二丁酯（DBP）已广泛应用于各种日用和工业产品的制造中。作为最重要的内分泌干扰物之一，DBP具有雄性生殖毒性，可导致睾丸功能障碍。鉴于睾丸间质细胞是睾丸中重要的功能和结构单位，它们的损伤会影响睾丸功能。然而，DBP对小鼠睾丸间质细胞造成损伤的潜在机制仍不清楚。在该研究中，通过体内和体外实验证实DBP可促进死亡相关蛋白激酶3（DAPK3）的表达，从而诱导小鼠睾丸间质细胞自噬。此外，利用生物信息学分析和分子生物学实验技术进一步证明，DBP诱导的DAPK3上调是由特异性蛋白2（Sp2）激活转录以及帕金RBR E3泛素蛋白连接酶（PRKN）导致的泛素化和降解减少所致。有趣的是，褪黑素可通过抑制氧化应激来抑制Sp2/DAPK3和PRKN/DAPK3信号通路，从而减轻DBP诱导的小鼠睾丸间质细胞自噬。总体而言，该研究揭示了DBP诱导小鼠睾丸间质细胞自噬的一种新的调控机制，并确定DAPK3是DBP对雄性生殖系统造成损伤的潜在治疗靶点。
