GSTM1 and GSTT1 null polymorphisms and male infertility risk: an updated meta-analysis encompassing 6934 subjects

Abstract

Published data on the association between the GST genes polymorphisms and male infertility risk are inconclusive. We investigated GST genes polymorphisms in a large sample size case-control study, and conducted a literature-based meta-analysis of 6934 individuals. Our case-control study showed the GSTM1 null genotype was significantly associated with idiopathic oligozoospermia, while the null genotype of GSTT1 was significantly associated with normozoospermia and azoospermia. Additionally, significantly elevated GSTT1 expression levels were observed in present genotype compared with null genotype. In the meta-analysis, the null genotype of GSTM1 was associated with a significantly increased risk of male infertility. Furthermore, a stratification analysis showed that the risk of GSTM1 polymorphism was associated with male infertility in both Asian and Caucasian groups. Further studies of GSTM1 and GSTT1 with their biological functions are needed to understand the role of these genes in the development of male infertility.I nfertility is a worldwide reproductive health problem which affects 10%-15% of couples and about half of the cases are due to male factors 1 . Although several causes have been identified for impaired male fertility 2 , the aetiology remains unknown in nearly half of all cases. It is currently accepted that genetics contributes to spermatogenetic failure for about 30% of idiopathic infertility in males 3 .Sperms are susceptible to oxidative damage and excessive reactive oxygen species (ROS) generation may lead to subfertility or infertility 4 . Glutathione S-transferases (GSTs) represent an important superfamily of phase II metabolic enzymes that catalyze the conjugation of reduced glutathione with electrophilic groups of a wide variety of environmental compounds. GSTs are responsible for detoxification of many xenobiotics and endogenous ROS by catalyzing the conjugation of reduced glutathione to the substrate or sequestering toxic compounds, and play a key role in protecting cells against oxidative stress 5 . Human GSTs are divided into eight distinct classes as alpha, kappa, mu, omega, pi, sigma, theta, and zeta based on the similarity of amino acid sequence and antibody cross-reactivity 6,7 . The GSTM1 and GSTT1 gene have been located on chromosome 1p13.3 and 22q11, respectively. Homozygotes for the null alleles (deletion) of GSTM1 and GSTT1 lack activity of the respective enzymes 8 . As a result, GSTs decrease the reactivity of electrophilic substrates, which can affect spermatogenesis and spermatozoa function with cellular macromolecules, such as nucleonic acid, lipid and protein.The enzymatic deficiency in isoforms of GSTs is correlated with increased risk to develop certain diseases associated with oxidative damage. In this case an association between the genotypes of GSTM1, GSTT1 and risk of idiopathic infertility is possible.Recently, a number of molecular epidemiological studies have been conducted to examine the association between GSTM1 and GSTT1 null polymorphisms and male infertil...

Genome-wide association study for semen volume and total number of sperm in Holstein-Friesian bulls

“…No. of Pages 5 deficiencies in humans (Aston and Carnell, 2009;Aston et al, 2010;Sang et al, 2011;Hu et al, 2011;Wu et al, 2013;Xu et al, 2013). Genes underlying the volume of semen and total number of sperm in ejaculate of fertile bulls were not studied.…”

The role of epigenetics in idiopathic male infertility

“…• 367 testis and epididymis specific hypomethylated genes • 134 hypermethylated [11] Global OAT (69)…”

“…Recently, some copy number variations (CNV) have been described to be associated with severe oligozoospermia or Sertoli-cell-only (SCO) syndrome or both [6]. In addition, some autosomal deletions, rare X-linked CNV, DNA repair mechanism defects, Y-linked syndromes, and some single nucleotide polymorphisms (SNPs) have been found to be associated with male factor infertility [7][8][9][10][11][12][13]. Although some specific mutations have been identified, other factors responsible for the sperm defects remain unknown.…”

Missense mutation in glutathione-S-transferase M1 gene is associated with sperm motility and ATP content in frozen-thawed semen of Holstein-Friesian bulls

“…Most findings confirmed its influence on sperm concentrations (Aydemir et al, 2007;Finotti et al, 2009;Olshan et al, 2010) but also on sperm motility and increased oxidative damage of sperm plasma membrane in idiopathic infertility patients with GSTM1 null genotype (Aydemir et al, 2007). GSTM1 null genotype has also been studied in relation to susceptibility to male infertility, particularly to idiopathic oligozoospermia (Wu et al, 2013) and oligoasthenoteratoa zoospermia (OAT) (Tang et al, 2012). Lakpour et al (2013) indicated however no associations between GSTM1 polymorphism and sperm parameters and seminal plasma antioxidant levels in infertile men with OAT.…”