Xenobiotic metabolism, genetic polymorphisms and male infertility

Abstract

Male reproductive function may be impaired by various occupational and environmental chemical agents. The majority of these xenobiotics, however, require metabolic activation in order to exert adverse effects via covalent interactions between intermediate metabolites and cellular macromolecules such as DNA or protein. In addition, metabolization may alter endocrine-disrupting properties of xenobiotics. Thus tissue-specific expression and regulation of multiple xenobiotic-metabolizing enzymes are likely to play an important role in chemically induced disorders of male reproductive organs. Recent studies suggest that genetic polymorphisms underlying inter-individual and inter-ethnic variability of xenobiotic metabolism modulate susceptibility to male reproductive disorders. For cytochrome P450 1A1 (CYP1A1), a key enzyme in extra-hepatic metabolic activation of lipophilic xenobiotics, increased frequencies of two genetically linked polymorphisms have been found among infertile men.

Glutathione S-transferase M1 and T1 polymorphism in men with idiopathic infertility

“…The polymorphism of GSTM1 and GSTT1 genes has been associated with male infertility (Schuppe et al, 2000) and also female infertility (Hadfield et al, 2001;Sata et al, 2003). When analyzing the genotype frequency within each group of normal and abnormal individuals from the semen sample, a statistically significant association was found between GST polymorphism and idiopathic male infertility.…”

“…Glutathione S-transferases (GSTs) constitute a superfamily of ubiquitous, multifunctional enzymes, which play a key role in phase II cellular detoxification and bioactivation reactions and are generally considered to be ''antioxidant'' enzymes (Schuppe et al, 2000;Hemachand and Shaha, 2003;Huber et al, 2008). These are widely expressed in mammalian tissues and have broad substrate specificity.…”

“…Genes encoding the GST Mu-1 and Theta-1 (GSTM1 and GSTT1, respectively) isoforms are polymorphic (Chen et al, 2002;Nakata et al, 2004). Homozygotes for the mutated inactive alleles of each gene are devoid of any specific enzymatic activity of GSTM1 or T1 (null genotypes) (Schuppe et al, 2000).…”

Synergism between the N-acetyltransferase 2 gene and oxidant exposure increases the risk of idiopathic male infertility

“…Polymorphic genes for xenobiotic-metabolizing enzymes are considered to be important modifiers of susceptibility to male infertility (Aydos et al, 2009;Rubes et al, 2010;Schuppe et al, 2000;Yarosh et al, 2013). Many studies have observed that functional polymorphisms in genes such as CYP1A1, GSTM1 and GSTT1 are associated with the risk of idiopathic male infertility (Aydos et al, 2009;Jaiswal et al, 2012;Polonikov et al, 2010;Safarinejad et al, 2010).…”

Developmental Expression and Endocrine Regulation of CYP1B1 in Rat Testis

“…The other set comprises those P450 enzymes, such as CYP1B1 (Otto et al, 1992), which play a major role in the biotransformation of hydrophobic xenobiotic compounds to more water-soluble metabolites. The physiological role of xenobioticmetabolizing P450 enzymes in testis is not definitively known, but it has been proposed that they catalyze the oxidative biotransformation of lipophilic xenobiotic or endogenous compounds within the testis, which has important implications for testicular toxicity (Schuppe et al, 2000).…”