Genetic susceptibility against environmental fators on male infertility

男性生殖功能受到各种环境因素的损害，如吸烟、热应激、内分泌干扰化学物质和氧化应激。异种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易感性。谷胱甘肽s -转移酶（GST） M1/T1的多态性是异种药物肝外代谢的关键酶，已被证明影响与吸烟等异种药物相关的男性不育的易感性。首先，在194名日本不育男性中调查了吸烟与GSTTI/M1多态性之间的关系。145例非阻塞性男性不育症患者中，85例（58.6%）男性为GSTM1零基因型。对照组和精子发生正常的不育患者GSTM1基因型分别为52.2%和55.1%。而GSTT1（+）的频率在非梗阻性男性不育和对照组之间无显著差异。在非梗阻性男性不育症中，精索静脉曲张患者GSTM1零基因型的频率高于对照组。这些初步结果表明，GSTM1零基因型可能与精索静脉曲张男性不育的个体易感性相关。其次，为了研究氧化应激和热应激对雄性不育的影响，我们研究了硫氧还蛋白转基因小鼠实验诱导的隐睾，该小鼠对各种类型的氧化应激具有细胞保护作用。在TRX转基因小鼠（TRX-tg）和野生型成年小鼠中手术诱导单侧隐睾，并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小鼠隐睾减重明显减少。此外，睾丸组织学和TUNEL染色显示，与WT小鼠相比，TRX-tg小鼠的凋亡变化延迟了4天。这些结果提示氧化应激与男性不育有关，氧化应激相关基因多态性可能与环境因素诱导男性不育的个体易感性有关

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