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Genetic susceptibility against environmental fators on male infertility

男性不育环境因素的遗传易感性

基本信息

批准号：
13671649
负责人：
YAMAMOTO Shingo
金额：
$ 2.24万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Male reproductive function is impaired by various environmental factors such as smoking, heat stress, endocrine-disrupting chemicals and oxidative stresses. There are inter-individual variability of xenobiotic metabolism, and genetic polymorphisms modulate susceptibility to male infertility associated with environmental factors. Polymorphisms of glutathione S-transferase (GST) M1/T1, key enzymes in the extrahepatic metabolism of xenobiotics, have been shown to influence susceptibility to male infertility associated with xenobiotics including smoking. First, the association between smoking and GSTTI/M1 polymorphisms were investigated in 194 infertile Japanese men. Of the 145 patients with non-obstructive male infertility, 85(58.6%) men had GSTM1 null genotype. Control population and infertile patients with normal spermatogenesis had GSTM1 null genotype in 52.2% and 55.1%. In contrast, the frequencies of GSTT1(+) is not significantly different between non-obstructive male infertility and … More control. Of non-obstructive male infertility, patients with varicocele had higher frequency of GSTM1 null genotype than control. These preliminary results suggest that the GSTM1 null genotype may be associated with individual susceptibility to male infertility associated with varicocele. Secondly, to investigate the effect of oxidative stress and heat stress on male infertility, we examined experimentally induced cryptorchid testes in thioredoxin transgenic mice, which have cytoprotective effects against various types of oxidative stresses. Unilateral cryptorchidism was surgically induced both in TRX transgenic (TRX-tg) and wild type adult mice, and testicular damage was evaluated by measuring testis weight and analyzing tcsticular histology. Weight reduction of cryptorchid testis was significantly decreased in TRX-tg mice, compared with those in wild type mice. Moreover, testicular histology and TUNEL staining demonstrated that apoptotic changes were delayed by 4 days in TRX-tg mice compared with those in WT mice. These results suggest that oxidative stress is associated with male infertility and polymorphisms of oxidative stress-related genes may be associated with individual susceptibility to male infertility induced by environmental factors Less

男性生殖功能受到各种环境因素的损害，如吸烟、热应激、内分泌干扰化学品和氧化应激。异生物质代谢存在个体间差异，遗传多态性调节与环境因素相关的男性不育的易感性。谷胱甘肽S-转移酶（GST）M1/T1基因多态性是外源性物质肝外代谢的关键酶，已被证明可影响与吸烟等外源性物质相关的男性不育的易感性。首先，在194名不育的日本男性中研究了吸烟与GSTTI/M1多态性之间的关联。在145例非梗阻性男性不育患者中，85例（58.6%）为GSTM 1缺失型。对照组和生精功能正常的不育患者GSTM 1基因缺失率分别为52.2%和55.1%。与此相反，GSTT 1（+）的频率在非梗阻性男性不育和 ...更多信息控制在非梗阻性不育男性中，精索静脉曲张患者GSTM 1缺失基因型频率高于对照组。这些初步结果表明，GSTM 1无效基因型可能与精索静脉曲张相关的男性不育的个体易感性。其次，为了研究氧化应激和热应激对男性不育的影响，我们检测了硫氧还蛋白转基因小鼠实验诱导的隐睾，其对各种类型的氧化应激具有细胞保护作用。通过手术诱导TRX转基因（TRX-tg）和野生型成年小鼠单侧隐睾，通过测量睾丸重量和分析睾丸组织学来评估睾丸损伤。与野生型小鼠相比，TRX-tg小鼠的隐睾睾丸重量减轻显著减少。此外，睾丸组织学和TUNEL染色表明，与WT小鼠相比，TRX-tg小鼠的凋亡变化延迟了4天。这些结果表明，氧化应激与男性不育有关，氧化应激相关基因的多态性可能与环境因素诱导的男性不育的个体易感性有关。