Maternal genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 and the risk of hypospadias

Abstract

Hypospadias is one of the most common congenital anomalies. Increased exposure to environmental factors (endocrine-disrupting chemicals and smoking) or maternal endogenous estrogen may cause hypospadias because male sexual differentiation is dependent on normal androgen homeostasis. Moreover, interactions between genetic factors and cigarette smoking and other chemicals have been suggested. It has been demonstrated that the CYP1A1 metabolizes not only environmental chemicals but also estrogens, and glutathione-S-transferases (GSTs) are detoxification enzymes that protect cells from toxicants by conjugation with glutathione. In this study, to investigate the association of CYP1A1 (MspI), GSTM1 and GSTT1 polymorphisms with hypospadias, a case-control study of 31 case mothers who had boys with hypospadias and 64 control mothers was performed in Japan. These polymorphisms were investigated by PCR-based methods using DNA from peripheral lymphocytes. We found that the heterozygous CYP1A1 and heterozygous and homozygous CYP1A1 were less frequent in the case mothers than in the control mothers [adjusted odds ratio (OR)=0.17, 95% confidence interval (CI)=0.04-0.74, OR = 0.28, 95% CI = 0.08-0.97, respectively]. We found no effect of maternal smoking on the hypospadias risks among the gene polymorphisms. The results suggest that mothers with the CYP1A1 MspI variant allele may have a decreased risk for hypospadias.

Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias

“…Genetic polymorphisms in these transcription factors and enzymes may be important in determining individual susceptibility to EED exposure and also in the development of MGMs. [13][14] Both our study, and other previous studies have identified that genetic variants for ESR1 and ESR2 could raise the susceptibility of CO and HS by enhancing the effects of estrogenic EEDs, which are known as xenoestrogens and currently the largest group of known EEDs. 7,15 In addition, several nuclear receptors, such as aryl-hydrocarbon receptor (AHR) and pregnane X receptor (PXR or NR1I2), are known to be crucial for EED-mediated CYP transcription.…”

“…CYP1A2 variants are in linkage disequilibrium with CYP1A1 alleles, which themselves have been previously associated with the risk of infertility and HS. 13 Moreover, CYP1A1 and CYP1A2 share many of the same enzymatic activities and may be under coordinated regulation; placental expression and activity of CYP1A1 seem to be greater than for CYP1A2 and to occur earlier in pregnancy. 41 However, we did not find any positive CYP1A1 variants in this study.…”

Dioxin-metabolizing genes in relation to effects of prenatal dioxin levels and reduced birth size: The Hokkaido study

“…Because we had observed an association between prenatal dioxin levels and AHR and CYP1A1 genotypes [14] and between prenatal smoking and maternal AHR, CYP1A1 and GSTM1 genotypes and reduced birth weight [22,31], we evaluated those three genetic polymorphisms in the present study. The AHR (G>A, rs2066853) and CYP1A1 (T>C, rs4646903) polymorphisms were determined using PCR [32,33]. GSTM1 null and non-null genotypes were determined using multiplex PCR [30,32].…”

Combined effects of AHR , CYP1A1 , and XRCC1 genotypes and prenatal maternal smoking on infant birth size: Biomarker assessment in the Hokkaido Study

“…The QIAamp DNA Blood Mini Kit (QIAGEN GmbH, Hilden, Germany) [30] and Maxwell 16 DNA Purification Kit (Promega, Madison, WI, USA) were isolate and purify DNA according to the manufacturer's instruction. AHR, CYP1A1, CYP1A2, CYP1B1, GSTM1 (+/-), and GSTT1 (+/-) polymorphisms were determined by the TaqMan PCR method as described [11,[31][32][33][34][35]. XRCC1 genotyping was performed using a 7300/7500 Real-Time PCR AmpErase UNG (Applied Biosystems) in a total volume of 10 µL.…”