| Infertility is a worldwide reproductive health problem which affects10%–15%of couples and about half of the cases are due to male factors. Several genetic causese.g. immunologic, endocrinopathies, gametogenesis dysfunction, ejaculatory failure,and environmental toxins of infertility have been identified in human. Nevertheless,the etiology of nearly half of all cases remains unknown. Men with idiopathic malefactor infertility diagnosed by subnormal semen parameters as defined by the WHO1999criteria, including oligospermia, teratospermia, asthenospermia, and nonobstructive azoospermia. idiopathic male infertility azoospermia, oligozoospermia,asthenospermia, teratozoospermia.Therefore, the genes related to spermatogenesis areconsidered as the important candidate for idiopathic male infertility. Humanspermatogenesis is a complex process in which a serial of cell function includingproliferation, meosis and differentiation are involved. It is eatimated that more than2000genes participated in spermatogenesis. With the advancement in gene function, a lot of genes related to spermatogenesis have been identified and characterized inrecent years.Glutathione S-transferases (GSTs) represent an important superfamily of phaseⅡmetabolic enzymes that catalyze the conjugation of reduced glutathione withelectrophilic groups of a wide variety of environmental compounds. GSTs is a verylarge gene families. GSTM1, GSTM3, GSTT1, GSTT2, GSTP1gene polymorphismsare thought to be associated with a variety of human diseases. GSTs are enzymes withdetoxifying properties that are ubiquitously expressed, with especially high levels inthe gonads, liver and colon. GSTs enzyme activity can affect spermatogenesis andsemen quality, leading to male infertility. The available data are not conclusive andfew studies appear to have addressed the issue of association of idiopathic maleinfertility with GSTs genes.In our case-control study, we evaluated whether GSTT1, GSTM1, GSTP1genesmay have a role in altering susceptibility to idiopathic male infertility.To correctlyrealize the correlation between the gene polymorphism and DNA methylation ofGSTs and idiopathic male infertility. To provide theoretical basis for the diagnosis andetiology study of male infertility.PartⅠ Glutathione S-Transferase M1(GSTM1) andGlutathione S-Transferase T1(GSTT1) null polymorphismsand the risk of idiopathic male infertilityObjectiveTo investigate association between the genetic polymorphisms of the glutathioneS-transferase M1, T1genes (GSTM1and GSTT1) and susceptibility of idiopathicinfertile male in Chinese population.Methods1. We undertook genotyping on a total of2371individuals including wellcharacterized infertile patients (n=1476) and confirmed fertile controls(n=895).Genomic DNA was analyzed by polymerase chain reaction (PCR) for GSTM1andGSTT1genes. 2. Multivariate logistic regression analysis was performed to examine the effectsof polymorphisms of GSTM1and GSTT1on idiopathic male infertility.3. Serum samples from well characterized infertile patients (n=33) andconfirmed fertile controls(n=42) were used to test the expression of GSTM1andGSTT1by using enzyme-linked immunosorbent assay (ELISA).Results1. Our case-control study showed statistically significant association of humanmale infertility with GSTT1null genotype (OR=1.26; P=0.007) but not withGSTM1null genotype.2. Next, the case group was subdivided into three subgroups: normozoospermia,oligozoospermia and azoospermia. GSTM1null genotype was significantly associatedwith idiopathic oligozoospermia (OR=1.55; P=0.004), while the null genotype ofGSTT1was significantly associated with normozoospermia (OR=1.23; P=0.025)and azoospermia (OR=1.58; P=0.002).3. In accordance with the results of our population study, significantly elevatedGSTT1expression levels were seen in present genotype compared with null genotype(P <0.001).Conclusion1. GSTM1null genotype may be associated with the susceptibility to idiopathicinfertile male.2. GSTT1null genotype may be associated with the susceptibility to idiopathicinfertile male and azoospermia.3. GSTT1null genotype may lead to reduce serum samples GSTT1activity, theninfluence the antioxidant ability of body, which lead susceptible to idiopathic infertilemale. PartⅡ: Glutathione S-Transferase P1(GSTP1)polymorphisms and DNA methylation and the risk ofidiopathic male infertilityObjectiveTo investigate association between the genetic polymorphisms and DNAmethylation of the glutathione S-transferase P1(GSTP1) and susceptibility ofidiopathic infertile male in Chinese population.Methods1. We undertook genotyping on a total of1972individuals including wellcharacterized infertile patients (n=1255) and confirmed fertile controls(n=717).Genomic DNA was analyzed by the TaqMan SNP Genotyping Assays for GSTP1gene.2. GSTP1gene CGI methylation patterns and idiopathic infertile men: using thebisulfite sequencing methods, we examined methylation patterns of GSTP1gene intesticular tissue DNA obtained from5NOA and5normal fertile controls.Results1. There was no significant difference in genotype distribution for the GSTP1variant between the idiopathic infertile subjects and fertile subjects in ourcase-control study.2. The percentage of methylation of5normal fertile controls:22.7%,55.5%,17.4%,62.8%and59.1%. The percentage of methylation of5NOA:89.1%,72.7%,71.6%,60.6%and84.5%. Subjects with higher methylation level ofGSTP1were more likely to have idiopathic male infertility (P<0.05).Conclusion1. GSTP1polymorphisms appear to be do not associated with increased risk ofidiopathic male infertility in Chinese population.2. Hypermethylation of GSTP1gene in testicular tissue is associated withidiopathic male infertility. |
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