Gene-gene and gene-environment interactions on risk of male infertility: Focus on the metabolites.

Abstract Infertility affects about 17% couples, and males contribute to half of the cases. Compared with independent effects of genetic and environmental factors, interactions between them help in the understanding of the susceptibility to male infertility. Thus, we genotyped 25 polymorphisms, measured 16 urinary chemical concentrations and explored interactions between gene-gene and gene-environment in 1039 Han Chinese using metabolomic analysis. We first observed that GSTT1 might interact with GSTM1 ( P inter  = 6.33 × 10 − 8 ). Furthermore, an interaction between GSTM1 and 4- n -octylphenol (4- n -OP) was identified ( P inter  = 7.00 × 10 − 3 ), as well as a 2-order interaction among GSTT1 , GSTM1 and 4- n -OP ( P inter  = 0.04). Subjects with GSTT1 -present and GSTM1 -null genotypes were susceptible to male infertility when exposed to 4- n -OP (OR = 14.05, 95% CI = 4.78–60.20, P  = 2.34 × 10 − 5 ). Most metabolites identified were involved in the tricarboxylic acid cycle. In conclusion, it is a novel study of the interaction on male infertility from the aspect of metabolomics.