硫化氢通过线粒体氧化应激介导特发性少、弱精子症发生的分子机制研究

Idiopathic oligoasthenozoospermia is a common type of male infertility, manifests itself by the reduction of number and vitality in sperm, but its specific pathogenesis has unknown. Studies have shown that oxidative stress in testis and semen is an important reason for the occurrence of oligoasthenozoospermia, and hydrogen sulfide is an antioxidant which can reduce the damage of mitochondrial oxidative stress. We found that CBS (hydrogen sulfide generating enzymes) was significantly decreased in testis of non-obstructive azoospermia patients. We decreased CBS/hydrogen sulfide levels could induced oligoasthenozoospermia in mice, that with the higher ROS level and lower ATP level in testis. They suggest that hydrogen sulfide may induced oligoasthenozoospermia by mitochondrial oxidative stress. Therefore, we will use molecular biology, immunology, genetics and other technology, from the morphology, quantity, permeability transition pore, energy metabolism, autophagy and apoptosis of mitochondria, to study the molecule mechanism of hydrogen sulfide in mice oligoasthenozoospermia by mitochondrial oxidative stress and verify in oligoasthenozoospermia patients in clinic. This research will provide theoretical basis for exploring the etiology and new treatments of idiopathic male infertility.

特发性少、弱精子症是男性不育的常见类型，主要表现为精子数量减少和活力低下，但其具体的发病机制至今不明。研究显示，睾丸组织和精液中的氧化应激是引起少、弱精子症发生的重要原因，而硫化氢是抗氧化剂，能减轻线粒体氧化应激的损伤。申请人前期研究发现硫化氢生成酶胱硫醚-β-合酶（CBS）在非梗阻性无精症患者睾丸组织中的表达显著降低，而下调CBS/硫化氢能够引起小鼠少、弱精子症的发生，且小鼠睾丸中ROS产生增多，ATP合成减少，提示硫化氢通过线粒体氧化应激介导少、弱精子症的发生。因此，本项目拟采用分子生物学、免疫学、遗传学等技术，从线粒体形态、数量、通透性转换孔、能量代谢、自噬和凋亡等方面着手，研究下调睾丸CBS/硫化氢通过线粒体氧化应激介导小鼠少、弱精子症发生的分子机制，并在临床上少、弱精子症患者的精液标本中进行验证。这将为找出特发性男性不育的发病原因和寻求新的治疗方法提供理论依据。

特发性少、弱精子症是男性不育的常见类型，主要表现为精子数量减少和活力低下，但其具体的发病机制至今不明。研究显示，睾丸组织和精液中的氧化应激是引起少、弱精子症发生的重要原因，而硫化氢是抗氧化剂，能减轻线粒体氧化应激的损伤。而硫化氢在特发性少、弱精子症中的作用和机制尚不清楚。本项目研究发现下调睾丸CBS/H2S可引起小鼠少、弱精子症的发生，明确了内源性CBS/H2S途径在少、弱精子症发生中的作用；发现下调小鼠睾丸CBS/H2S途径后，会导致Mn-SOD活性下降，引起ROS过量存在，从而导致线粒体呼吸链氧化磷酸化过程中线粒体复合体I中的NADH脱氢酶和线粒体复合体IV中的细胞色素C氧化酶表达减少，致使复合体I、III、IV活性降低，引起ATP生成减少，最终导致小鼠少精、弱精的发生，已初步阐明线粒体介导的内源性CBS/H2S途径在少、弱精子症发生中的调控机制；通过对临床少、弱精子症患者精液的研究，发现外源性补充H2S可以改善精子活力，这为探讨特发性男性不育的发病原因和治疗策略提供新的线索和切入点。