Genetic variation in the Nrf2 promoter associates with defective spermatogenesis in humans.
Defective spermatogenesis, which severely impairs male fertility, can be caused by excessive reactive oxygen species (ROS). Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates transcription of genes encoding enzymes important for protection against ROS. In human seminal plasma and spermatozoa, superoxide dismutase isoenzymes (SOD) and glutathione S-transferases (GST) are key antioxidant enzymes. We hypothesized that decreased function of the Nrf2-antioxidant response element (ARE) pathway might predispose individuals to male infertility. In this study, we identified three functional single nucleotide polymorphisms (SNPs) in the Nrf2 promoter regions of 196 idiopathic asthenozoospermic patients, 140 idiopathic oligoasthenozoospermic patients, and 295 controls. We found that two of the Nrf2 SNPs (-617 G > T and -653 T > C) were associated with oligoasthenozoospermia (p = 0.001) and individuals with 617 TT and 653 TT genotypes had higher risk of oligoasthenozoospermia (p = 0.006 and p = 0.002). Four haplotypes of Nrf2 promoters were identified, and two of them (GCC and TCT) had different frequencies in oligoasthenozoospermic patients than in controls (p = 0.019 and p = 0.011). In vitro reporter assay indicated that oligoasthenozoospermia associated genotypes of Nrf2 had significantly decreased transcriptional capabilities. The GCC and TCT haplotypes both showed lower Nrf2 mRNA expression in spermatozoa than GCT. TCT also showed decreased levels of antioxidant gene GSTM1 and SOD2 mRNA. Analysis of total seminal SOD activity elucidated that oligoasthenozoospermic patients had less SOD activity than controls. This study is the first to demonstrate a strong association between functional polymorphisms in Nrf2 promoters with defective spermatogenesis in humans.
Key Laboratory for Major Obstetric Diseases of Guangdong Province, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
Bolan
B
Yu
Huanlan
H
Lin
Lixia
L
Yang
Kang
K
Chen
Haihua
H
Luo
Jianqiao
J
Liu
Xingcheng
X
Gao
Xuefeng
X
Xia
Zhaofeng
Z
Huang
D000328:Adult; D053627:Asthenozoospermia / Q000235:genetics; D017930:Genes, Reporter; D014644:Genetic Variation; D005838:Genotype; D005982:Glutathione Transferase / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species; D012306:Risk; D012907:Smoking; D013091:Spermatogenesis / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D005982:Glutathione Transferase