Mol. Hum. Reprod. Advance Access originally published online on December 3, 2004
Molecular Human Reproduction 2005 11(2):93-98; doi:10.1093/molehr/gah134
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Maternal genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 and the risk of hypospadias
1Department of Public Health, 2Department of Renal and Genitourinary Surgery and 3Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan
4 To whom correspondence should be addressed. Email: noriek{at}med.hokudai.ac.jp
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Abstract |
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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.
Key words: CYP1A1/genetic polymorphism/GSTM1/GSTT1/hypospadias
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Introduction |
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Hypospadias, a common congenital anomaly, is the incomplete fusion of the urethral folds resulting in a urethral opening on the ventral surface of the penis or on the scrotum or the perineum.
In recent decades, a number of epidemiological studies have reported an increase in prevalence of hypospadias over time in various countries (Imaizumi et al., 1991
; Paulozzi, 1999; Sumiyoshi et al., 2000a,b). The prevalence of hypospadias varies widely in different countries and populations, ranging from 0.37 to 41 per 10 000 infants (Kallen et al., 1986). The prevalence of hypospadias in Hokkaido, Japan is 3.9 per 10 000 infants (Kurahashi et al., 2004). The aetiology of hypospadias is complex, involving genetic, hormonal and environmental factors. As male sexual differentiation is critically dependent on normal androgen concentrations, increased exposure to environmental factors [i.e. endocrine-disrupting chemicals (EDCs) with estrogenic or anti-androgenic effects] or maternal endogenous estrogen affecting androgen homeostasis during fetal life may cause hypospadias (Sharpe and Skakkebaek, 1993; Sharpe, 2001; Sultan et al., 2001).
For some specific malformations such as cleft palate, a positive association between maternal smoking and these malformations has been reported, and the finding has been repeated by independent investigators (Werler, 1997; Kallen, 2002). Cigarette smoke contains hazardous compounds, such as benzo[a]pyrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), nicotine, benzene, toluene, etc. (US Department of Health, Education, and Welfare, 1964; Muto and Takizawa, 1989; Brunnemann and Hoffmann, 1991), and these substances were thought to be one of the factors inducing malformations.
The detoxification of cigarette smoke depends on two phases of metabolism. In phase I metabolism, the reactive intermediates are produced. The CYP1A1 is a well-studied phase I enzyme. The CYP1A1 m2 allele has a T
C mutation in the 3' non-coding region, which is highly induced by certain toxic environmental chemicals such as benzo[a]pyrene (Jaiswal et al., 1985) and 2,3,7,8-TCDD (Whitlock, 1990). Moreover, it has been demonstrated that the CYP1A1 metabolizes not only environmental chemicals but also endogenous estrogens (Nebert and Gonzalez, 1987; Kristensen and Borresen-Dale, 2000). The CYP1A1 is involved in the metabolism of estradiol by catalysing the C-2 hydroxylation (Michnovicz and Rosenberg, 1992). The mutation in this region has been suggested to lead to higher enzyme activity (Landi et al., 1994; Mitrunen and Hirvonen, 2003), and some previous papers reported that the variant CYP1A1 is protective for breast cancer, in which it is well established that estrogens play an important role (da Fonte de Amorim et al., 2002; Miyoshi et al., 2002; Hefler et al., 2004). In phase II, these metabolic intermediates are detoxified by conjugating enzymes. Glutathione-S-transferases (GSTs) are phase II detoxification enzymes that protect cells from toxicants by conjugation with glutathione (Awasthi et al., 1994). Inherited homozygous deletion of these genes has been demonstrated to result in lack of this detoxification activity (Pemble et al., 1994; Yu et al., 1995). There are ethnic differences in the frequency of genetic polymorphisms in biotransformation enzymes (Kawajiri et al., 1990; Cosma et al., 1993; London et al., 1995; Garte, 1998). Variant alleles of each mutation are associated with enhanced susceptibility to several diseases, especially to lung cancer in Japanese smokers (Kawajiri et al., 1990).
Maternal smoking or exposure to some chemicals during pregnancy may affect the development of the genitourinary system because the toxic compounds may directly reach the embryo. Another possibility is that the effects of toxicants on the embryo may be modified by maternal biotransformation enzyme activity because of the genetic polymorphisms in the CYP1A1, GSTM1 or GSTT1 genes.
We hypothesized that the maternal genetic susceptibility to smoking might influence the risk for hypospadias. Therefore, we performed a case–control study to investigate the association of maternal CYP1A1, GSTM1 and GSTT1 polymorphisms with hypospadias risk in a Japanese population.
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Materials and methods |
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Patients
This case–control study was performed in the cities of Sapporo and Nagoya, Japan, during the years 2000–2004. In this study, the eligible cases were defined as mothers who had male children operated on for hypospadias at the Department of Urology of Hokkaido University Hospital or Chukyo Hospital between 2001 and 2004. The controls were mothers who delivered male children without any malformation at the Department of Obstetrics of Hokkaido University Hospital between 2000 and 2003. We studied 31 case mothers and 64 control mothers. All the cases and the controls were women of Japanese ethnicity.
We used a self-administered questionnaire. Maternal characteristics that we assessed included maternal age at delivery, smoking history at the time of pregnancy and educational level. Infant characteristics included weight at delivery and whether they had any malformation or not. We also collected information on the patients about the severity of hypospadias from the hospital records. Hypospadias is classified as mild (distal) when the opening of the urethra is in the glandular, coronal or penile portion, and as severe (proximal) when the opening of the urethra is in the penoscrotal, scrotal or perineal portion. The urologists who operated on the patients classified the degree of hypospadias.
This study was conducted with all the subjects' informed consent and approved by the institutional ethical board for human gene and genome studies of the Hokkaido University Graduate School of Medicine.
Genetic analysis
Genomic DNA was extracted from lymphocytes of peripheral blood samples by standard techniques. The CYP1A1, GSTM1 and GSTT1 genotypes were detected by PCR for GSTM1 and GSTT1, and PCR–restriction fragment length polymorphism (PCR–RFLP) for CYP1A1. We have not studied any other genetic variant, apart from the three described.
The presence or absence of the GSTM1 and GSTT1 genes was determined as described by Chen et al. (1996) with slight modifications. Briefly, an aliquot of 100 ng of DNA was mixed with 0.5 µmol/l each of the primers (GSTM1 forward, 5'-GAA CTC CCT GAA AAG CTA AAG C-3' and reverse, 5'-GTT GGG CTC AAA TAT ACG GTG G-3'; GSTT1 forward, 5'-TTC CTT ACT GGT CCT CAC ATC TC-3' and reverse, 5'-TCA CCG GAT CAT GGC CAG CA-3'), and 0.2 mol/l each of ß-globin primers (forward, 5'-CAA CTT CAT CCA CGT TCA CC-3' and reverse, 5'-GAA GAG CCA AGG ACA GGT AC-3'), 1.25 IU of Taq polymerase (AmpliTaq Gold; Applied Biosystems Japan, Tokyo, Japan) with 3.3 mmol/l MgCl2 and 200 µmol/l dNTP in a total volume of 50 µl of PCR buffer provided by the manufacturer. The PCR procedure was as follows: an initial denaturation step at 94°C for 12 min, and then amplification for 40 cycles at 94°C for 15 s, 60°C for 30 s and 72°C for 1 min, followed by a final extension step at 72°C for 7 min. Genotyping of the MspI polymorphism in the 3' non-coding region of the CYP1A1 gene was determined by PCR–RFLP, as previously described (Hayashi et al., 1991; Oyama et al., 1995) with slight modifications. Briefly, an aliquot of 100 ng DNA was mixed with 0.5 µmol/l of each primer (CYP1A1 forward, 5'-CAG TGA AGA GGT GTA GCC GC-3' and reverse, 5'-TAG GAG TCT TGT CTC ATG CC-3'), 1.25 IU of Taq polymerase (AmpliTaq Gold; Applied Biosystems Japan, Tokyo, Japan) with 3.3 mmol/l MgCl2 and 200 µmol/l dNTP in a total volume of 50 µl of PCR buffer provided by the manufacturer. The PCR procedure was as follows: an initial denaturation step at 95°C for 10 min, and then amplification for 35 cycles at 95°C for 30 s, 61°C for 30 s and 72°C for 30 s, followed by a final extension step at 72°C for 7 min. The PCR products for GSTM1 and GSTT1 were analysed by 3% agarose gel electrophoresis and those for CYP1A1 were digested with the restriction enzyme MspI (Promega Corp., USA), separated by gel electrophoresis (3% agarose) and identified with ethidium bromide staining. We confirmed that there was no contamination using a no-template control.
Statistical analysis
Odds ratios (OR) and 95% confidence intervals (CI) values were calculated to estimate the risk of hypospadias associated with the factors studied, using unconditional logistic regression analysis. We analysed crude OR in all the 31 case mothers and 64 control mothers using three separate models. In order to control confounding factors, such as maternal age at delivery, birth weight and maternal smoking during pregnancy, we applied a multivariate logistic regression risk analysis in 24 case mothers and 64 control mothers who fully answered the questionnaire. All analyses were conducted using Statistics Package for Social Sciences (SPSS Inc., USA) software for Windows.
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Results |
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The OR of hypospadias, according to child and maternal characteristics, are given in Table I. We found a significant positive association between low birth weight (<2500 g) and hypospadias (OR = 7.22, 95% CI = 2.56–20.39). The OR for women of 35 years of age or older compared with younger ones was 3.00 (95% CI = 0.97–9.30). Maternal smoking during pregnancy did not appear to be associated with the risk of hypospadias.
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The frequencies of the GSTM1, GSTT1 and CYP1A1 genotypes were compared between the 31 case mothers and the 64 control mothers in a Japanese population (Table II). Heterozygous CYP1A1 (m1/m2) and heterozygous and homozygous CYP1A1 (m1/m2+m2/m2) were less frequently found in the case mothers than in the control mothers (crude OR = 0.31, 95% CI = 0.11–0.84, OR = 0.42, 95% CI = 0.17–1.02, respectively). On the other hand, there was no significant evidence that the distribution of the GSTM1 and GSTT1 genotypes differed between the case and the control mothers (crude OR = 1.34, 95% CI = 0.56–3.22 and OR = 0.75, 95% CI = 0.31–1.82, respectively). After adjusting for maternal age at delivery, birth weight and maternal smoking during pregnancy, the lower risk of hypospadias associated with the CYP1A1 m1/m2 and CYP1A1 m1/m2+m2/m2 genotypes (OR = 0.17, 95% CI = 0.04–0.74 and OR = 0.28, 95% CI = 0.08–0.97, respectively) (Table III) were significant. The adjusted ORs of GSTM1 and GSTT1 did not change significantly compared with crude ORs in Table II. If correction for multiple comparisons (Bonferroni) among the three genes was done, results did not remain significant.
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We found no effects of maternal smoking on the hypospadias risks among the gene polymorphisms (Table IV). Smokers with the GSTM1 and GSTT1 null genotypes showed an increased risk of hypospadias (OR = 2.36, 95% CI = 0.39–14.41 and OR = 1.28, 95% CI = 0.20–4.14, respectively), but not significantly. The proportions of the CYP1A1 m1/m2+m2/m2 genotypes in case mothers seemed to be lower than in controls regardless of whether they were smokers or non-smokers (smokers with the CYP1A1 m1/m2+m2/m2 genotype: OR = 0.54, 95% CI = 0.07–4.33 and non-smokers with the CYP1A1 m1/m2+m2/m2 genotype: OR = 0.42, 95% CI = 0.10–1.79, respectively). Smokers with the CYP1A1 m1/m1 genotype showed a decreased risk of hypospadias (OR = 0.77, 95% CI = 0.12–4.98), but not significantly.
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We also investigated the association of the severity of hypospadias and mothers' polymorphisms (Table V). We did not find any significant association between the severity and the GSTM1. The GSTM1 null genotype showed a slightly increased risk of severe type of hypospadias (mild type: OR = 0.84, 95% CI = 0.20–3.47, severe type: OR = 2.94, 95% CI = 0.39–21.97, respectively), but it was not significant. The proportion of the GSTT1 null in case mothers who had children with severe hypospadias was lower than in controls (OR = 0.22, 95% CI = 0.02–1.97). Similarly, the proportions of the CYP1A1 m1/m2+m2/m2 genotypes in case mothers who had mildly or severely hypospadiac children were lower than in controls (mild type: OR = 0.26, 95% CI = 0.06–1.14, severe type: OR = 0.21, 95% CI = 0.03–1.60, respectively), but not significantly.
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Discussion |
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In our study, we found that the frequency of low birth weight was significantly higher in hypospadias. The CYP1A1 m1/m2 or m1/m2+m2/m2 genotype was found to be associated with significantly decreased risk of hypospadias. We found no significant association between smoking and hypospadias risk.
Recently, risk factors for hypospadias have been reported in several epidemiological case–control studies. Hussain et al. (2002) reported that there was a significant association of hypospadias with poor intrauterine growth. Gatti et al. (2001) reported that the incidence of hypospadias in small-for-gestational-age infants admitted to the NICU was 10 times higher than that in the general population. Hughes et al. (2002) reported that the mean birth weight in boys with hypospadias was lower than in control boys. We also found that the low birth weight was associated with an elevated risk of hypospadias. This result was consistent with similar findings by others as mentioned above.
As far as we know, this is the first study to report an association with hypospadias and maternal genetic polymorphisms in biotransformation enzymes. We found that mothers with the CYP1A1 m1/m2+m2/m2 genotype showed a decreased risk for hypospadias (Table II). It is well known that the aryl hydrocarbon hydroxylase (AHH) is involved in the metabolism and detoxification of a variety of aryl hydrocarbon compounds, and that CYP1A1 controls the activity of AHH (Crofts et al., 1994; Landi et al., 1994; Kiyohara et al., 1996). On the other hand, it has been demonstrated that CYP1A1 metabolizes not only environmental chemicals but also endogenous estrogens (Nebert and Gonzalez, 1987; Kristensen and Borresen-Dale, 2000). CYP1A1 was recently shown to confer an imbalance in estrogen metabolism, leading to production of the apparently inactive metabolite 2-OH estrogen (Taioli et al., 1999). CYP1A1 mutations have been suggested to lead to higher enzyme activity (Landi et al., 1994; Mitrunen and Hirvonen, 2003). Previous papers studied an association between the variant CYP1A1 and breast cancer, in which it is well established that the estrogens play an important role in carcinogenesis and progression. Although, some studies reported that mutant CYP1A1 was a major risk factor in breast cancer (Taioli et al., 1995; Ishibe et al., 1998; Huang et al., 1999), other studies have reported that it is protective against it (da Fonte de Amorim et al., 2002; Miyoshi et al., 2002; Hefler et al., 2004). Moreover, Niwa et al. (1998) suggested that the CYP1A1 was responsible for the hydroxylation of endogenous steroids, including progesterone, pregnenolone, dehydroepiandrosterone (DHEA) and/or estrone. Thus, these results suggest that the metabolites of estrogens or other hormones through CYP1A1 might be critical for developing hypospadias, because normal urethral development depends on the delicate balance of these hormones (Husmann and Cain, 1994; Yucel et al., 2003).
GSTs are phase II detoxification enzymes that protect cells from toxicants by conjugation with glutathione (Awasthi et al., 1994). However, we could not find any associations between hypospadias (which was not classified by severity) and each GST gene.
Our results became non-significant when multiple testing is taken into consideration (Bonferroni correction). However, this correction is a controversial matter because type II errors (the probability of accepting a null hypothesis, when it is actually false) tend to increase in an attempt to cut down type I errors (the probability of rejecting the null hypothesis, when it is indeed true) by applying the Bonferroni correction. This means that significant results are lost and the power of the study is reduced (Perneger, 1998).
Several researches have reported the relation between smoking susceptibility and adverse health effects for infants. Wang et al. (2002) reported that the children of smoking mothers who had the CYP1A1 MspI variant genotypes and the GSTT1 deletion genotype had low birth weights compared with reference groups. Van Rooij et al. (2001) reported mothers who smoked and had the GSTT1 null genotype had an increased risk for having a child with oral clefting, compared with non-smokers with the wild-type genotype, but there was no interaction between the CYP1A1 and the maternal smoking in relation to oral clefting. In our study, even after adjusting for maternal age at delivery, maternal smoking during pregnancy and low birth weight, we showed that the CYP1A1 m1/m2 or m1/m2+m2/m2 genotype decreased the risk for hypospadias (Table III). Although we used a smaller number of subjects for calculating adjusted OR in Table III than that for calculating crude OR in Table II, the results did not change significantly. This result suggested that the CYP1A1 m1/m2 or m1/m2+m2/m2 genotype was an independent and protective factor for hypospadias. Moreover, we found no effect of maternal smoking on the hypospadias risks among the gene polymorphisms (Table IV). The reasons may be that the size of our study population and the proportion of women who smoked during pregnancy were too small to determine whether there was any significant difference. This finding suggests that there was no significant association between the CYP1A1 polymorphism with maternal smoking during pregnancy and hypospadias may also suggest that this polymorphism contributes to induction of hypospadias through the metabolism of endogenous sex hormones, such as estrogen, progesterone and testosterone rather than environmental chemicals.
Kalloo et al. (1993) reported that the corpus cavernosum and the stroma of the inner prepuce, scrotum and periphery of the glans were androgen receptor (AR)-rich, but that the epithelia of the preputial skin, penile shaft skin and scrotal skin were AR negative in human male fetuses at 18–22 weeks gestation. Thus, the difference of distribution of AR in the male external genitalia and the difference of hypospadiac severity might reflect sensitivity to chemical compounds, such as EDCs or endogenous sex hormones. The proportion of the GSTT1 null was different in our results in which we analysed all hypospadias compared with those after dividing cases by the severity of hypospadias (Table V). The proportion of the GSTT1 null in the case mothers who had children with severe hypospadias was lower than for mild hypospadias and controls. However, the proportions of the CYP1A1 m1/m2 and m2/m2 genotypes were the same for all hypospadias and after classifying by severity. Our results might suggest that the GSTT1 genotype is involved in severe hypospadias and sensitivity to chemical compounds.
In this study, our results suggested an association between the genetic polymorphism in CYP1A1 and the risk for hypospadias. Our finding provides evidence that a maternal genetic factor related to biotransformation enzymes and estrogen metabolism may affect the risk of hypospadias. However, the sample size in this study was relatively small. In future, further molecular epidemiological studies with a larger population need to be performed to more clearly elucidate maternal genetic risk factors for hypospadias.
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Acknowledgements |
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We thank Dr Y Tsuji, of Chukyo Hospital, for allowing us access to patients. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and the Japan Ministry of Health, Labour and Welfare.
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Submitted on October 19, 2004; accepted on November 10, 2004.
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