Mol. Hum. Reprod. Advance Access originally published online on August 6, 2004
Molecular Human Reproduction 2004 10(10):729-733; doi:10.1093/molehr/gah096
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Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not involved in the risk of recurrent pregnancy loss
1Department of Public Health and 2Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan
3 To whom correspondence should be addressed. Email: y-saijo{at}med.hokudai.ac.jp
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Abstract |
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The etiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in four genes, human aryl hydrocarbon (Ah) receptor, cytochrome P450 (CYP) 1A1, CYP1A2 and CYP1B1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. All cases and controls were women resident in Sapporo, Japan and the surrounding area. The Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes were assessed in 113 Japanese women with recurrent pregnancy loss (RPL) and 203 ethnically matched women experiencing at least one live birth and no spontaneous abortion (control). No significant differences in Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotype frequencies were found between the women with RPL and the controls [Ah receptor: Arg/Arg (reference); Arg/Lys and Lys/Lys, odds ratio (OR)=0.67; 95% confidence interval (CI)=0.40–1.11, CYP1A1: m1m1 (reference); m1m2 and m2m2, OR = 0.86; 95% CI = 0.53–1.40, CYP1A2: C/C and C/A (reference); A/A, OR = 1.16; 95% CI = 0.71–1.88, CYP1B1: Leu/Leu (reference); Leu/Val and Val/Val, OR = 1.18; 95% CI = 0.68–2.02]. The present study suggests that the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not major genetic regulators in RPL.
Key words: Ah receptor/CYP1A1/CYP1A2/CYP1B1/recurrent pregnancy loss
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Introduction |
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About 10–14% of clinically recognized pregnancies end in pregnancy loss in the Japanese population, as in Caucasians. The etiology of recurrent pregnancy loss (RPL) remains largely unclear (Stirrat, 1990
; Parazzini et al., 1991; Cramer and Wise, 2000; Yamada et al., 2001). Epidemiological studies have suggested that the condition might be multifactorial with a possible genetic predisposition and involvement of environmental factors in its pathogenesis (Fenster et al., 1991; Parazzini et al., 1991; Cramer and Wise, 2000).
Enzymes belonging to cytochrome P450 (CYP) families are involved in the two-stage detoxification process of a wide range of environmental toxins and carcinogens. The genes for these enzymes are part of the Ah gene battery and are under Ah receptor control (Nebert and Gonzalez, 1987). The Ah receptor binds a number of different classes of chemicals, including halogenated aromatics such as dioxin and polycyclic aromatic hydrocarbons, which induce transcription of the genes in this battery (Safe, 1995).
RPL is believed to be associated with various environmental toxins and teratogens such as organic solvents, alcohol, heavy metals and ionizing radiation, but scientifically accurate information regarding the reproductive impact of potential environmental toxins and other teratogens is not readily available (Gardella and Hill, 2000). Maternal exposure to dioxin has been associated with increases in fetal loss and reduction in birth weight in experimental studies in rodents and monkeys (Courtney, 1976; Allen et al., 1979; Murray et al., 1979; McNulty, 1984; Nau et al., 1986; Umbreit et al., 1987; Bjerke et al., 1994). Most halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are initiated by their binding to Ah receptor. Following ligand binding, the Ah receptor dimerizes with Ah receptor nuclear translocator, and thereby acquires the ability to interact with dioxin response elements that enhance transcription of genes encoding CYP1A1, CYP1A2 and CYP1B1. Each of these enzymes is inducible in human cells by halogenated aromatic hydrocarbons via the Ah receptor pathway (Li et al., 1998) and each can convert activated forms of them (Larsen et al., 1998; Turesky et al., 1998; Williams and Phillips, 2000).
Recent studies have demonstrated that the CYP family gene polymorphisms significantly influence reproductive conditions. Wang et al. (2002) reported that CYP1A1 gene polymorphism was associated with a reduction in birth weight among women who smoked cigarettes in the United States. We previously demonstrated that CYP17 gene polymorphism was associated with risks of RPL (Sata et al., 2003b) and intrauterine fetal growth restriction in the Japanese population (Yamada et al., 2004).
The aim of this study was to investigate whether the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms which are associated with impaired detoxification were related to the pathogenesis of RPL.
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Materials and methods |
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This case-control study was performed in the city of Sapporo, Japan, during the years 1999–2003. We studied 113 patients aged 20–43 years with a history of RPL and 203 controls aged 21–49 years who were obstetrically managed in the Hokkaido University Hospital. The characteristics of the study groups are shown in Table I. RPL was defined as having a history of two or more spontaneous consecutive abortions and stillbirths of less than 25 weeks of gestation. The primary RPL group comprised 99 women with a history of two or more spontaneous abortions but no live birth. The 14 secondary RPL women experienced three or more spontaneous abortions after at least one live birth. A total of 105 miscarriages occurred in the first trimester. All women with RPL were subjected to examination by ultrasound and hysterosalpingography for detection of anatomical abnormalities of the genital tract and to chromosome karyotypic analyses of peripheral blood. Couples who had balanced type chromosomal translocation and women with a uterine conformational abnormality such as septate uterus were excluded from this study. The control women consisted of 203 volunteers experiencing at least one live birth, no spontaneous abortion and no history of endometriosis or infertility. There were no significant differences in age between cases and controls. This study was conducted with all the subjects' informed consent and approved by the institutional ethical board for human gene and genome studies of Hokkaido University Graduate School of Medicine.
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Peripheral blood samples were thawed at room temperature, and after thorough vortexing, 200 µl were used to extract genomic DNA. QIAamp DNA Blood Mini Kit (QIAGEN GmbH, Hilden, Germany) was used to purify DNA in accordance with the manufacturer's instructions. The detailed method for the detection of the CYP1A1 MspI polymorphism can be found elsewhere (Wu et al., 1999
). This method is able to detect all three possible genotypes for the polymorphism: m1m1 (homozygous wild-type), m1m2 (heterozygous variant type) and m2m2 (homozygous variant type).
To analyze the CYP1A2/D polymorphism, PCR amplifications were carried out as described by Christiansen et al. (2000), using the primers 5-GGAAGGTATCAGCAGAAAGCC-3' and 5-GGCTCATCCTTGACAGTGCC-3. After the PCR product was digested with ApaI endonuclease, the restriction digest was separated in a 3% agarose gel, generating a 255 bp fragment and a 371 bp fragment. The 626 bp fragment represented the ‘A’ allele (variant type). The 255 bp and 371 bp fragments represented the ‘C’ allele (wild-type).
Ah receptor and CYP1B1 gene polymorphisms were determined by the TaqMan polymerase chain reaction (PCR) method using MGB (Minor Groove Binder) probe (de Kok et al., 2002). To detect a polymorphism of Ah receptor at codon 554 G/A (Arg/Lys), two MGB probes were prepared; a G allele specific probe, 5'-FAM-CATGTGTCTGATGTCT-MGB-3', and an A allele specific probe, 5'-CTGCATGTGTTTGAT-MGB-3'. Each of the reporters was quenched by MGB, which was typically located at the 3' end. The design of primers for PCR of the flanking region of the G/A polymorphism in Ah receptor was as follows: forward, 5'-CAGCATAATGAAAAACCTAGGCATT-3'; reverse, 5'-CATCCGTTAAGTCAATGTCTCTCAA-3'. PCR was carried out using thermal cycler GeneAmp® PCR System 9700 (Applied Biosystems, Foster City, USA). During PCR cycles (initial denaturation at 95°C for 10 min after 50°C for 2 min, followed by 40 cycles of 92°C for 30 s and 60°C for 60 s), the fluorescence level of PCR products was measured using an ABI PRISM 7000 Sequence Detector (Applied Biosystems), resulting in the clear identification of three genotypes of Ah receptor. To detect a polymorphism of CYP1B1 at codon 432 C/G (Leu/Val), two MGB probes were prepared; a G allele specific probe, 5'-FAM-ACCCAGTGAAGTGG-MGB-3', and C allele specific probe, 5'-ATGACCCACTGAAGTG-MGB-3'. The design of primers for PCR of the flanking region of the C/G polymorphism in CYP1B1 was as follows: forward, 5'-TGTCAACCAGTGGTCTGTGAATC-3'; reverse, 5'-TCACTCTGCTGGTCAGGTCCTT-3'. PCR was carried out employing the same PCR conditions as for Ah receptor analysis.
We calculated age-adjusted odds ratios (OR) and 95% confidence intervals (CI) associated with the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes by unconditional logistic regression analysis. Hardy–Weinberg equilibrium analyses were performed to compare observed and expected genotype frequencies using a chi-square test. All analyses were conducted using SPSS software for Windows version 12.0 (SPSS Inc., Chicago, IL).
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Results |
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The characteristics of the study groups are shown in Table I. The frequencies of the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes in 113 cases with RPL were compared with those in 203 controls in the Japanese population (Table II). The distributions of all genotypes in each group were in Hardy–Weinberg equilibrium. There was no significant difference in Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotype frequencies between the women with RPL and the controls. The genotype frequencies of Ah receptor, CYP1A1, CYP1A2 and CYP1B1 in our control population resembled those published earlier in Japan (Chida et al., 1999
; Watanabe et al., 2001; Kiyohara et al., 2003; Sasaki et al., 2003).
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We next evaluated the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes in both subgroups of women with three or more pregnancy losses (PLs) (Table III). There was no significant difference in Ah receptor, CYP1A1, CYP1A2 or CYP1B1 genotype frequencies between the women with RPL with three or more PLs and the controls.
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Discussion |
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The codon 554 G/A polymorphism in the Ah receptor gene appears to be a determinant of the level of CYP1A1 inducibility in the Caucasian population (Smart and Daly, 2000
). However, no association was found between this polymorphism and levels of CYP1A1 activity or lung cancer susceptibility in the Japanese population (Kawajiri et al., 1995). CYP1A1 is involved in the metabolic activation of benzo[a]pyrene, a widely distributed environmental carcinogen, which is found in tobacco smoke. Maternal CYP1A1 MspI polymorphism was found to be associated with a reduction in birth weight among women who smoked cigarettes, suggesting an interaction between metabolic genes and environmental factors (Wang et al., 2002). The authors demonstrated that mothers who smoked cigarettes and carried the m2 allele of CYP1A1 had a greater risk of delivering low birth-weight infants, while among mothers who had never smoked neither genotype had an influence on birth weights of their infants. It is suggested that CYP1A1 MspI variant genotypes increase enzyme activity (Landi et al., 1994).
CYP1A2 is involved in the metabolic activation of numerous chemical carcinogens—heterocyclic and aromatic amines and nitroaromatic compounds (Eaton et al., 1995) and in the biotransformation of many xenobiotics. CYP1A2 genotype A/A had a higher CYP1A2 inducibility than genotype G/A and G/G (Sachse et al., 1999). It was reported that a high CYP1A2 activity was associated with the risk of spontaneous abortion, and that caffeine intake positively related to the increased risk of spontaneous abortion among women with high CYP1A2 activities (Signorello et al., 2001). Serum levels of one of the caffeine metabolites, paraxanthine, was found to relate to an increased risk of spontaneous abortion (Klebanoff et al., 1999). CYP1B1 also is involved the metabolic activation of benzo[a]pyrene (Luch et al., 1998) and converts estrogens to 4-hydroxy estrogens that induced DNA damage (Tang et al., 1996). The 4-hydroxylation activity of 432G (variant) enzyme was 3-fold higher than the 432C (wild) enzyme. Associations between the 432G and breast cancer (Hanna et al., 2000) and endometrial cancer (Sasaki et al., 2003) were reported.
Recently, many investigations demonstrated that the maternal gene polymorphisms related to RPL risks without consideration of burdens of environmental factors (Yamada et al., 2004); these genes included factor V Leiden and prothrombin mutations (Rey et al., 2003), plasminogen activation inhibitor I and factor XIII (Dossenbach-Glaninger et al., 2003), HLA-G (Aldrich et al., 2001; Pfeiffer et al., 2001), GSTM1 (Sata et al., 2003a), IL-1 (Unfried et al., 2001; Wang et al., 2002; Karhukorpi et al., 2003), IL-6 (Saijo et al., 2004), CYP17 (Sata et al., 2003b) and NOS3 (Tempfer et al., 2001). It is likely that RPL is a multifactorial polygenetic disease. In the current study, however, no significant relationships between RPL and Ah receptor, CYP1A1, CYP1A2 or CYP1B1 polymorphisms were found; these gene polymorphisms involved in altered detoxification ability were not major genetic regulators in RPL when RPL risks were assessed without consideration of the burdens of environmental factors.
Experimental animal studies have demonstrated that maternal exposure to dioxin is associated with fatal loss and reduction in birth weight. However, there are few epidemiological studies of the association between the maternal dioxin exposure and pregnancy outcome in humans; and a study of the population exposed to a high level of dioxin in Seveso showed no significant association between TCDD exposure and adverse pregnancy outcome (Eskenazi et al., 2003). Another recent study found no association between blood dioxin levels and the CYP1A1 MspI polymorphism, although the sample size of this study was relatively small (n=28) (Tsuchiya et al., 2003). Metabolic pathways of xenobiotics include their activation during phase I of the biotransformation process followed by conjugation of highly toxic intermediate metabolic products during phase II (Baranova et al., 1999). The presence of deletions of phase II enzymes such as GSTM1 rather than polymorphic phase I enzymes including AhR batteries can deeply provoke imbalanced interactions of phase I and II (Sata et al., 2003a). Unfortunately, we did not evaluate the dioxin exposure levels in the current study. Therefore, further studies are needed to clarify whether the association between maternal dioxin exposure and pregnancy outcome can be modified by xenobiotic gene polymorphisms.
The number of cases and controls in our study had 80% power to detect a true OR of 2.5, 2.1, 2.0, 2.1 for Ah receptor, CYP1A1, CYP1A2 and CYP1B1, respectively, at the 0.05 significance level according to the genotype frequencies of our control group (Browner et al., 2001). In order to elucidate the role of AhR gene battery and their gene polymorphisms and to prove gene–environmental relationships in the RPL pathophysiology, further studies are needed, taking into account environmental factors such as cigarette smoking, caffeine intake and dioxin exposure.
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Acknowledgements |
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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. We thank Ms Sakuramachi, Mr Haraguchi, Ms Abe, Ms Tanabe and Ms Kunita for their technical assistance.
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Submitted on June 1, 2004; resubmitted on July 5, 2004; accepted on July 11, 2004.
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F. Sata, H. Yamada, K. Suzuki, Y. Saijo, E. H Kato, M. Morikawa, H. Minakami, and R. Kishi Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss Mol. Hum. Reprod., May 1, 2005; 11(5): 357 - 360. [Abstract] [Full Text] [PDF]
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