Copper deposition in Wilson's disease causes male fertility decline by impairing reproductive hormone release through inducing apoptosis and inhibiting ERK signal in hypothalamic-pituitary of mice.
Copper deposition in Wilson's disease causes male fertility decline by impairing reproductive hormone release through inducing apoptosis and inhibiting ERK signal in hypothalamic-pituitary of mice.
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DOI：
10.3389/fendo.2022.961748
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发表时间：
2022
影响因子：
5.2
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中科院分区：
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威尔逊病（WD）是一种常染色体隐性铜代谢疾病，以肝脏和中枢神经系统功能障碍为特征。大量证据表明，男性WD患者不孕症也很常见，但确切的分子机制尚不清楚。为了进一步探讨下丘脑-垂体-睾丸（HPT）轴的病理改变及其机制，将小鼠分为正常对照组（NC）、WD模型TX组（WD）、二巯基琥珀酸处理TX组（DMSA）和孕马血清促性腺激素处理TX组（PMSG）。对雌性小鼠下丘脑和垂体组织的铜含量、形态、下丘脑神经元和垂体促性腺激素细胞的超微结构和凋亡、血清生殖激素水平、妊娠率和产仔数进行了研究。检测下丘脑和垂体细胞凋亡相关蛋白的表达和细胞外调节蛋白激酶（ERK） 1/2的磷酸化水平。结果显示，WD组大鼠铜含量显著升高，下丘脑和垂体组织病理形态和超微结构受损。促性腺激素释放激素、促卵泡激素、促黄体生成素和睾酮水平显著降低。下丘脑和垂体细胞凋亡率明显升高。促凋亡蛋白Bax、Caspase-3表达显著升高，抗凋亡蛋白Bcl-2表达显著降低，ERK1/2磷酸化水平显著降低。生育率显著下降。DMSA干预后，下丘脑组织铜含量降低，下丘脑和垂体组织形态超微结构改善，细胞凋亡减轻，Bax和Caspase-3表达显著降低，Bcl-2表达显著升高，生殖激素水平、磷酸化水平和生育能力升高。经PMSG处理后，雄性TX小鼠的生育能力得以保留。上述结果提示，铜在WD中的沉积可能通过诱导细胞凋亡和抑制下丘脑-垂体区ERK信号，从而影响生殖神经内分泌激素的释放，从而导致雄性生育能力下降。本研究也可为铜污染对男性生殖系统的危害提供参考。
Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism characterized by liver and central nervous system dysfunction. Considerable evidence suggests that infertility is also very common in male patients with WD, but the exact molecular mechanisms involved remain unknown. In order to further investigate the pathological changes in the hypothalamic-pituitary-testicular (HPT) axis and its mechanisms, mice were divided into the normal control group (NC), WD model TX mice group (WD), dimercaptosuccinic acid–treated TX mice group (DMSA), and pregnant horse serum gonadotropin–treated TX mice group (PMSG). The copper content and morphology of hypothalamus and pituitary tissues, the ultrastructure and apoptosis of hypothalamus neurons and pituitary gonadotropin cells, the serum levels of reproductive hormones, and the pregnancy rate and litter size of the female mice were studied. The expression of apoptosis-related proteins and the phosphorylation of extracellular regulatory protein kinase (ERK) 1/2 in the hypothalamus and pituitary were detected. The results showed that the copper content was significantly increased in the WD group, and the histopathological morphology and ultrastructure of the hypothalamus and pituitary were damaged. The levels of the gonadotropin-releasing hormone, the follicle-stimulating hormone, the luteinizing hormone, and testosterone were significantly decreased. The apoptosis rate in the hypothalamus and pituitary was significantly increased. The expressions of proapoptotic proteins Bax and Caspase-3 were significantly increased, the expression of the anti-apoptotic protein Bcl-2 was significantly decreased, and the phosphorylation level of ERK1/2 was significantly decreased. Fertility is significantly reduced. After DMSA intervention, the hypothalamus tissue copper content decreased, the hypothalamus and pituitary tissue morphology and ultrastructure were improved, cell apoptosis was alleviated, the expression of Bax and Caspase-3 was significantly decreased, the expression of Bcl-2 was significantly increased, and the reproductive hormone level, phosphorylation level, and fertility were increased. Fertility was preserved after treatment with PMSG in male TX mice. These results suggest that copper deposition in WD causes male fertility decline by impairing reproductive neuroendocrine hormone release through inducing apoptosis and inhibiting the ERK signal in the hypothalamic–pituitary region. This study can also provide reference for the damage of copper pollution to the male reproductive system.