Ali Waseem, Behan Atique Ahmed, Ma Yonggang, Chen Yan, Zheng Hao, Liu Zongping, Zou Hui
College of Veterinary Medicine, Yangzhou University, Yangzhou, China.
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China.
J Mol Histol. 2025 May 28;56(3):177. doi: 10.1007/s10735-025-10463-x.
Cadmium is a toxic heavy metal, disrupts different cellular secretions and induce pathological changes in the male reproductive system. However, cadmium-induced disruption of exosomal secretion and cellular pathways in Leydig cells is largely unknown. In this study, 30 C57BL/6 male mice were divided into two groups: one receiving purified water and the other 50 mg/L CdCl2 for three months. This is a first report, both in vivo and in vitro analyses showed that the control group exhibited strong immunoreactivity and immunosignaling with high secretion of exosomal proteins CD63 and multivesicular bodies (MVBs) through immunohistochemistry, immunofluorescence, and transmission electron microscopy. Leydig cells in the control group maintained a normal steroidogenic pathway, supporting the production of healthy, motile spermatozoa. Conversely, the cadmium-treated group showed irregularly dispersed Leydig cells with condensed nuclei and vacuolated mitochondria. Cadmium exposure led to reduced immunoreactivity, immunosignaling, and expression of CD63 in Leydig cells, with a noticeable lack of MVBs secretion. Additionally, cadmium significantly down-regulated the Steroidogenesis regulatory proteins STAR, CYP11A1, CYP17A1, 3BHSD1, 17BHSD1 and AR of Leydig cells. It also disrupted autophagic flux evidenced by increased expression of ATG5, ATG7, LC3, P62, and LAMP2 proteins. Furthermore, cadmium up-regulated apoptotic proteins (Caspase-3, Caspase-8, and Bax) and down-regulated the anti-apoptotic protein Bcl-2. This study provides novel insights into the detrimental effects of cadmium on Leydig cells' secretory pathways, highlighting disruptions in exosomal-MVBs secretion, autophagy and apoptosis, thereby posing significant risks to male fertility.
镉是一种有毒重金属，会干扰不同的细胞分泌，并在雄性生殖系统中引发病理变化。然而，镉诱导的睾丸间质细胞外泌体分泌和细胞信号通路的破坏在很大程度上尚不清楚。在本研究中，30只C57BL/6雄性小鼠被分为两组：一组饮用纯净水，另一组饮用50mg/L氯化镉，持续三个月。这是首份报告，体内和体外分析均表明，通过免疫组织化学、免疫荧光和透射电子显微镜观察，对照组显示出较强的免疫反应性和免疫信号，外泌体蛋白CD63和多囊泡体（MVBs）分泌量较高。对照组的睾丸间质细胞维持正常的类固醇生成途径，有助于产生健康、有活力的精子。相反，镉处理组的睾丸间质细胞分布不规则，细胞核浓缩，线粒体空泡化。镉暴露导致睾丸间质细胞免疫反应性、免疫信号和CD63表达降低，MVBs分泌明显缺乏。此外，镉显著下调睾丸间质细胞的类固醇生成调节蛋白STAR、CYP11A1、CYP17A1、3BHSD1、17BHSD1和AR。它还破坏了自噬流，这通过ATG5、ATG7、LC3、P62和LAMP2蛋白表达增加得以证明。此外，镉上调凋亡蛋白（Caspase-3、Caspase-8和Bax）并下调抗凋亡蛋白Bcl-2。本研究为镉对睾丸间质细胞分泌途径的有害影响提供了新见解，突出了外泌体-MVBs分泌、自噬和凋亡的破坏，从而对男性生育能力构成重大风险。
