Increased oxidative damage of sperm and seminal plasma in men with idiopathic infertility is higher in patients with glutathione S-transferase Mu-1 null genotype

Aim： To examine whether a relationship exists between glutathione S-transferase Mu-1 （GSTM1） gene polymorphism and the susceptibility of sperm and seminal plasma from patients with idiopathic infertility to oxidative stress. Methods： Fifty-two men with idiopathic infertility and 60 healthy fertile men were recruited to this study. GSTM1 gene polymorphism was determined by polymerase chain reaction （PCR） and both the infertile and control individuals were divided into GSTM1 null and GSTM1 positive groups according to their GSTM1 gene structure. We compared reactive oxygen species （ROS） generation, malondialdehyde （MDA）, protein carbonyls and glutathione （GSH） concentrations, and glutathione S-transferase （GST） activity in seminal plasma and spermatozoa from infertile patients and controls with respect to GSTM1 genotype. Results： Significantly higher levels of oxidative stress and damage markers were found in idiopathic infertile men with the GSTM1 null genotype compared with those with the GSTM1 positive genotype. There was no significant difference in genotype distribution for theGSTM1 variant between the idiopathic infertile subjects and fertile subjects. Patients with the GSTM1 null genotype also had lower sperm concentrations than those with GSTM1 positive genotype. Conclusion： Our results suggest that the susceptibility of sperm and seminal plasma to oxidative stress is significantly greater in idiopathic infertile men with the GSTM1 null genotype compared with those possessing the gene. Therefore, in patients with idiopathic infertility, GSTM1 polymorphism might be an important source of variation in susceptibility of spermatozoa to oxidative damage.

Glutathione S-transferase genetic polymorphisms and fluoride-induced reproductive toxicity in men with idiopathic infertility

Male infertility caused by idiopathic oligoasthenospermia(OAT)is known as idiopathic male infertility.Glutathione S-transferase(GST)and fluoride may play important roles in idiopathic male infertility,but their effects are still unknown.Our study examined the relationship between GST polymorphisms and fluoride-induced toxicity in idiopathic male infertility and determined the underlying mechanism.Sperm,blood,and urine samples were collected from 560 males.Fluoride levels were measured by a highly selective electrode method,and GST genotypes were identified using polymerase chain reaction(PCR)and PCR-restriction fragment length polymorphism(PCR-RFLP).Semen parameters,DNA fragmentation index(DFI),mitochondrial membrane potential(MMP),and oxidative stress(OS)biomarkers were statistically assessed at the P<0.05 level.Compared with healthy fertile group,semen parameters,fluoride levels,OS biomarkers,sex hormone levels,and MMP and DFI levels were lower in the idiopathic male infertility group.For glutathione S-transferase M1(GSTM1[-])and glutathione S-transferase T1(GSTT1[-])or glutathione S-transferase P1(GSTP1)mutant genotypes,levels of semen fluoride,OS,MMP,and DFI were considerably higher,and the mean levels of sperm parameters and testosterone were statistically significant in GSTM1(+),GSTT1(+),and GSTP1 wild-type genotypes.Both semen and blood fluoride levels were associated with oxidative stress in idiopathic male infertility patients.Elevated fluoride in semen with the genotypes listed above was linked to reproductive quality in idiopathic male infertility patients.In conclusion,GST polymorphisms and fluorine may have an indicative relationship between reproductive quality and sex hormone levels,and OS participates in the development of idiopathic male infertility.

Folate and vitamin B12 in idiopathic male infertility

Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B12 （B12） and total homocysteine （tHcy）-related genes and measured these metabolites in blood. We conducted a case-control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmo and Lund, Sweden. Serum folate, red cell folate （RCF）, serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/ homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase （PEMT） M 175V and TCblR rs173665 polymorphisms were significantly associated with infertility （P=0.01 and P=0.009, respectively）, but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men （12.89 vs. 14.73 nmoll^- 1 P=0.02）, but there were no significant differences in RCF, B 12 or tHcy. Folate, B 12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMTand TCbIR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.

Exploring the potential impact of nutritionally actionable genetic polymorphisms on idiopathic male infertility:a review of current evidence

Infertility affects about 15%of the world's population.In 40%-50%of infertile couples,a male factor underlies the problem,but in about 50%of these cases,the etiology of male infertility remains unexplained.Some clinical data show that lifestyle interventions may contribute to male reproductive health.Cessation of unhealthy habits is suggested for preserving male fertility;there is growing evidence that most preexisting comorbidities,such as obesity and metabolic syndrome,are highly likely to have an impact on male fertility.The analysis of genetic polymorphisms implicated in metabolic activity represents one of the most exciting areas in the study of genetic causes of male infertility.Although these polymorphisms are not directly connected with male infertility,they may have a role in specific conditions associated with it,that is,metabolic disorders and oxidative stress pathway genes that are potentially associated with an increased risk of male infertility due to DNA and cell membrane damage.Some studies have examined the impact of individual genetic differences and gene-diet interactions on male infertility,but their results have not been synthesized.We review the current research to identify genetic variants that could be tested to improve the chances of conceiving spontaneously through personalized diet and/or oral vitamin and mineral supplementation,by examining the science of genetic modifiers of dietary factors that affect nutritional status and male fertility.

Strong association of SLCIA1 and DPF3 gene variants with idiopathic male infertility in Han Chinese

Male infertility is a multifactorial syndrome encompassing a wide variety of disorders. In recent years, several genome-wide single-nucleotide polymorphism （SNP） association studies （GWAS） have been performed on azoospermia and/or oligozoospermia in different populations including two GWAS on nonobstructive azoospermia in China; however, the association of SNPs with idiopathic male infertility, especially asthenozoospermia and oligozoospermia, and their correlation with semen parameters are still not clear. To investigate genetic variants associated with idiopathic male infertility （asthenozoospermia, oligozoospermia, and oligoasthenozoospermia） in Chinese Han people, 20 candidate SNPs were selected from GWAS results and genotyped using the Sequenom MassARRAY assay. A total of 136 subfertile men and 456 healthy fertile men were recruited, rs6476866 in SLCIA1 （P = 1.919E-4, OR = 0.5905, 95% Ch 0.447-0.78） and rs10129954 in DPF3 （P = 0.0023, OR = 2.199, 95% Ch 1.311-3.689） were strongly associated with idiopathic male infertility. In addition, positive associations were observed between asthenozoospermia and rs215702 in LSM5 （P= 0.0016, OR = 1.479, 95% CI： 1.075-2.033） and between oligoasthenozoospermia and rs2477686 in PEXIO （P= 0.0011, OR = 2.935, 95% Ch 1.492-5.775）. In addition, six SNPs （rs215702 in LSMS, rs6476866 in SLCIA1, rs10129954 in DPF3, rs1801133 in MTHFR, rs2477686 in PEXIO, and rs10841496 in PED3A） were significantly correlated with semen quality alterations. Our results suggest that idiopathic male infertility in different ethnic groups may share the same mechanism or pathway. Cohort expansion and further mechanistic studies on the role of genetic factors that influence spermatogenesis and sperm progressive motility are suggested.

Association of polymorphisms in glutathione S-transferase genes （GSTM1, GSTT1, GSTP1） with idiopathic azoospermia or oligospermia in Sichuan, China

The reported effects of the glutathione S-transferase （GSTs） genes （GSTM1, GSTTI, and GSTP1） on male factor infertility have been inconsistent and even contradictory. Here, we conducted a case-control study to investigate the association between functionally important polymorphisms in GST genes and idiopathic male infertility. The study group consisted of 361 men with idiopathic azoospermia, 118 men with idiopathic oligospermia, and 234 age-matched healthy fertile male controls. Genomic DNA was extracted from the peripheral blood, and analyzed by polymerase chain reaction and restriction fragment length polymorphism analysis. There was a significant association between the GSTP1 variant genotype （lle/Val ＋ Val/Val） with idiopathic infertility risk （odds ratio [OR]： 1.53; 95% confidence interval [CI]： 1.11-2.11; P = 0.009）. Similarly, a higher risk of infertility was noted in individuals carrying a genotype combination of GSTTI-null and GSTP1 （lle/Val ＋ ValNal） （OR： 2.17; 95% Cl： 1.43-3.31; P = 0.0002）. These results suggest an increased risk of the GSTPI variant genotype （lle/Val ＋ Val/Val） for developing male factor infertility. Our findings also underrate the significance of the effect of GSTM1 and/or GSTT1 （especially the former） in modulating the risk of male infertility in males from Sichuan, southwest China.