Mol. Hum. Reprod. Advance Access originally published online on February 15, 2006
Molecular Human Reproduction 2006 12(2):77-83; doi:10.1093/molehr/gal013
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Maternal smoking during pregnancy and genetic polymorphisms in the Ah receptor, CYP1A1 and GSTM1 affect infant birth size in Japanese subjects
1Department of Public Health, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan and 2Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo 060-0818, Japan
3 To whom correspondence should be addressed at: Department of Public Health, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan. E-mail: sasakis{at}med.hokudai.ac.jp
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Abstract |
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Genetic susceptibility to tobacco smoke might have relation to adverse pregnancy outcomes. To estimate the effects of maternal smoking and genetic polymorphisms on infant birth weight and length, we conducted a prospective cohort study of 293 women who delivered singleton live births in Sapporo, Japan. Birth weight and length were significantly lower among infants born to continuously smoking women having the aryl hydrocarbon receptor (AhR) wild type genotype (Arg/Arg; 211 g ± 76 g; 1.2 cm ± 0.4 cm, p < 0.01 and p < 0.01, respectively), the CYP1A1 variant genotype (m1/m2 + m2/m2; 170 g ± 64 g, 0.8 cm ± 0.3 cm, p < 0.01 and p < 0.05, respectively), or the GSTM1 null genotype (171 g ± 58 g, 0.6 cm ± 0.3 cm, p < 0.01 and p < 0.05, respectively). When combinations of these genotypes were considered, birth weight and length were significantly lower for infants of continuously smoking women in the AhR wild type + CYP1A1 variant group (315 g ± 116 g; 1.7 cm ± 0.6 cm, p < 0.01 and p < 0.01, respectively) and in the CYP1A1 variant + GSTM1 null group (237 g ± 92 g; 1.3 cm ± 0.5 cm, p < 0.05 and p < 0.01, respectively). These genotypes did not confer adverse effects among women who had never smoked; therefore, maternal smoking in combination with maternal AhR, CYP1A1 and GSTM1 genetic polymorphisms may adversely affect infant birth size.
Key words: Ah receptor/CYP1A1/fetal development/GSTM1/maternal smoking
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Introduction |
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Maternal smoking during pregnancy has adverse effects on both the mother and the fetus (Cnattingius, 2004
), and smoking is causally associated with pregnancy complications including placental abruption and placenta previa, preterm delivery, intrauterine growth retardation (IUGR) and fetal death. An infant whose mother continues to smoke throughout pregnancy is estimated to have twice the risk of low birth weight (LBW) compared with infants of non-smokers (Lieberman et al., 1994; Cliver et al., 1995; Haug et al., 2000; Windham et al., 2000; England et al., 2001a, 2001b; Jauniaux et al., 2001; Källén, 2001; Ohmi et al., 2002).
Tobacco smoke is a complex mixture of over 4000 compounds including nicotine, carbon monoxide and polycyclic aromatic hydrocarbons (PAHs). Nicotine causes placental vessels to contract, and carbon monoxide binds to fetal haemoglobin resulting in fetal hypoxemia (Bush et al., 2000). PAHs are both genotoxic and carcinogenic, and the amount of PAHs bound to DNA (PAH–DNA adducts) reflects the net effects of exposure, absorption, activation, detoxification and repair, which have been extensively used to measure the individual biologically effective dose of PAHs (Perera et al., 1998). Prior studies indicate that maternal PAH–DNA adduct levels in leukocytes are significantly higher in current smokers compared with both non-smokers and ex-smokers; furthermore, transplacental exposure to PAHs at relatively high concentrations has been associated with adverse birth outcomes, for example, infants with elevated levels of PAH–DNA adducts in leukocytes have significantly decreased birth weight, length and head circumference compared to infants with lower levels (Perera et al., 1999).
Aryl hydrocarbon receptor (AhR) mediates toxicity of xenobiotic chemicals, including PAHs and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as well as the induction of three members of the CYP1 family, CYP1A1, CYP1A2 and CYP1B1, and certain Phase II enzymes in humans (Anttila et al., 2001; Smith et al., 2001; Wong et al., 2001a, 2001b; Harper et al., 2002; Lin et al., 2003). Of these, CYP1A1 is a well-studied Phase I enzyme whose metabolic function results in PAHs activation. Furthermore, GSTM1 encodes a major Phase II enzyme that helps detoxify PAHs. Deficiency in GSTM1 activity is caused by homozygous deletion of GSTM1 (Hayes et al., 2000). Genetic polymorphisms in enzymes that metabolize xenobiotics have been shown to modulate the degree of cancer risk. For example, the MspI restriction fragment length polymorphism (RFLP) identified in the 3' non-coding region of CYP1A1 has been associated with lung cancer in Japanese smokers, and case–control studies have demonstrated that individuals having the GSTM1 null genotype have increased risk of lung cancer (Nakachi et al., 1993; Kihara et al., 1995, 1999; Stücker et al., 2000, 2002; Chen et al., 2001; Goldman et al., 2001; Wang et al., 2003). It has been suggested that factors, including metabolic enzymes, that mediate maternal genetic susceptibility to tobacco smoke might be related to adverse birth outcomes, and certain maternal genotypes, such as those involving the genes CYP1A1 or GSTT1, have been shown to enhance the association between maternal smoking and infant birth weight in a population in the United States (Wang et al., 2002; Nukui et al., 2004). However, there are few published reports on maternal genetic susceptibility to tobacco smoke in relation to birth size in Asian populations.
The aim of the present study was to investigate maternal genetic polymorphisms that affect the association between maternal smoking during pregnancy and infant birth weight and length among Japanese subjects. We characterized genetic susceptibility by analysing polymorphisms in the genes AhR, CYP1A1, GSTM1 and GSTT1.
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Materials and methods |
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Study population and data collection
A prospective cohort study was conducted between 2002 and 2004 in Sapporo, Japan (Hokkaido Study on Environment and Children’s Health). Study subjects were 373 women who enrolled at 23–35 weeks of gestation and delivered singleton live births at the Sapporo Toho Hospital and the participation rate was about 30%. A self-administered questionnaire was used to obtain relevant information including demographic characteristics, smoking history, alcohol consumption during pregnancy and household income. Information from maternal and infant medical records included pregnancy complications and birth outcomes (gestational age at birth, infant gender and birth weight and length). Women having gestosis, a history of diabetes mellitus or a multiple birth were excluded from the study. In this study, maternal smoking status was based on maternal self-reporting and categorized into two groups: non-smokers—those who did not smoke throughout pregnancy and smokers—those who continued to smoke during pregnancy. Although data from 80 women who quit smoking in the first or second trimester were not used in the analysis, other characteristics of these excluded women, such as maternal weight before pregnancy, height, parity or gestational age at birth, were similar to those of the non-smoking group.
This study was conducted with informed consent of all subjects and was approved by the institutional ethical board for human gene and genome studies of the Hokkaido University Graduate School of Medicine.
Genotyping methods
Maternal blood samples were collected at the time of study enrollment, and genomic DNA was extracted from lymphocytes by standard techniques (Saijo et al., 2004). The AhR polymorphisms were determined by the TaqMan PCR method using minor groove binder (MGB) probes, as described previously (Saijo et al., 2004). Briefly, to detect a polymorphism in AhR involving an arginine (Arg) to lysine (Lys) substitution at codon 554 (G/A) in exon 10, we prepared a G allele-specific MGB probe, 5'-FAM-CAT GTG TCT GAT GTC T-MGB-3' and an A allele-specific MGB probe, 5'-CTG CAT GTG TTT GAT-MGB-3'. Each of the reporters was quenched by excess MGB. Primers for PCR of the flanking region of the G/A polymorphism in AhR were as follows: forward, 5'-CAG CAT AAT GAA AAA CCT AGG CAT T-3' and reverse, 5'-CAT CCG TTA AGT CAA TGT CTC TCA A-3'. PCR was carried out using a thermal cycler (GeneAmp® PCR System 9700, Applied Biosystems, Foster City, USA). During PCR cycles (an initial denaturation at 95°C for 10 min followed by 50°C for 2 min, followed by 40 cycles of 92°C for 15 s and 60°C for 60 s), the fluorescence of PCR products was measured using an ABI PRISM 7000 Sequence Detector (Applied Biosystems), resulting in the clear identification of three AhR genotypes. The CYP1A1 T
C transition in the 3' non-coding region was determined using the PCR method described previously (Kurahashi et al., 2005). Briefly, 100 ng of 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'-TGA GAG TCT TGT CTC ATG CC-3'), 1.25 IU of Taq polymerase with 3.3 mmol/l MgCl2 and 200 µmol/l dNTP in a total volume of 50 µl containing PCR buffer provided by the manufacturer (AmpliTaq Gold; Applied Biosystems Japan, Tokyo, Japan). 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 CYP1A1 were digested with the restriction enzyme MspI (Promega Corp., USA), separated by 3% agarose gel electrophoresis and identified by ethidium bromide staining. A multiplex PCR method was used to detect the presence or absence of GSTM1 and GSTT1 genes, as described previously (Sata et al., 2003; Kurahashi et al., 2005). Briefly, 100 ng of DNA was mixed with 0.5 µmol/l of each primer (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') or, as a positive internal control, 0.2 mol/l each of ß-globin primers (forward, 5'-CAA CTT CAT CCA CGT TCA CG -3' and reverse, 5'-GAA GAG CCA AGG ACA GGT AC-3'), 1.25 IU of Taq polymerase with 3.3 mmol/l MgCl2 and 200 µmol/l dNTPs in a total volume of 50 µl containing PCR buffer provided by the manufacturer (AmpliTaq Gold). 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. The PCR products were separated by 3% agarose gel electrophoresis and identified by ethidium bromide staining.
Statistical methods
Associations between variables were analysed by the Student’s t-test and chi-square test. The multiple linear regression model was used to evaluate the individual and combined associations of maternal smoking status during pregnancy and the maternal genetic polymorphisms in relation to infant birth weight and length with adjustment for the following covariates: maternal age, weight before pregnancy, height, alcohol consumption during pregnancy (g/day), parity (0 and 
1), infant gender, gestational age at birth and household income. All statistical analyses were performed using the Statistics Package for Social Sciences (SPSS, Inc., USA) software for Windows version 12.0 J.
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Results |
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The analysis included 293 women: 220 ‘non-smokers’ and 73 ‘smokers’. The prevalence of smoking during pregnancy was 19.6% and these women reported smoking an average of 13.3 (range 1–30) cigarettes per day. In this study, the number of LBW infants was 14 (4.8%) and the number of small for gestational age (SGA, defined as birth weight <10th percentile) was 5 (1.7%). Demographic variables and genotype frequencies for the study group are summarized in Table I. The mean maternal age, infant birth weight and birth length were significantly lower in smokers (p < 0.01, p < 0.01 and p < 0.05, respectively). The two groups differed with regard to infant gender and household income (p < 0.05 and p < 0.05, respectively), with smokers having a lower percentage of male babies (38% versus 52% for non-smokers) and a lower overall income. Though the difference of household income might impact on maternal nutritional status and we have made no attempt to estimate maternal calorie intake during pregnancy, there was no statistically significant difference between the smoking and non-smoking groups with regard to the maternal weight gain during pregnancy (p = 0.240). Seventy non-smokers (31.8%) and 26 smokers (35.6%) drank alcohol during pregnancy. The amount of alcohol consumption was significantly higher in smokers (p < 0.01); however, infant birth weight and birth length did not differ significantly between non-drinkers and drinkers (p = 0.625 and p = 0.358, respectively) and between non-drinking and drinking smokers (p = 0.224 and p = 0.154, respectively). The distribution of the AhR and CYP1A1 genotypes in the 293 women satisfied the Hardy–Weinberg equilibrium (chi-square test, p = 0.845 and p = 0.777, respectively). Genotype frequency did not differ significantly between the smokers and non-smokers. As shown in Table II, multiple linear regression showed that continuous maternal smoking during pregnancy was associated with both lower infant birth weight (mean reduction of 135 g ± 43 g, p < 0.01) and length (mean reduction of 0.5 cm ± 0.2 cm, p < 0.05) after adjusting for the covariates.
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Table III summarizes the effects of continuous maternal smoking during pregnancy on infant birth weight and length, as categorized by maternal metabolic genotypes. When the AhR genotype was considered, the estimated reduction in birth weight and length was 211 g ± 76 g (p < 0.01) and 1.2 cm ± 0.4 cm (p < 0.01), respectively, for the wild type homozygous genotype group (Arg/Arg). For the CYP1A1 genotype, the estimated reduction in birth weight and length was 170 g ± 64 g (p < 0.01) and 0.8 cm ± 0.3 cm (p < 0.05), respectively, for the heterozygous or variant homozygous genotype group (m1/m2 + m2/m2). For the GSTM1 genotype, the estimated reduction in birth weight and length was 171 g ± 58 g (p < 0.01) and 0.6 cm ± 0.3 cm (p < 0.05), respectively, for the null genotype group. There was no statistically significant difference between the smoking and non-smoking groups with regard to the GSTT1 null genotype.
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Table IV presents the combined associations of continuous maternal smoking during pregnancy and maternal AhR, CYP1A1 and GSTM1 genotypes with regard to infant birth weight and length. When the AhR and CYP1A1 genotypes were considered, the estimated reduction in birth weight and length was 315 g ± 116 g (p < 0.01) and 1.7 cm ± 0.6 cm (p < 0.01), respectively, among smokers with the AhR wild type and CYP1A1 variant genotype groups. For the combination of the CYP1A1 and GSTM1 genotypes, the estimated reduction in birth weight and length was 237 g ± 92 g (p < 0.05) and 1.3 cm ± 0.5 cm (p < 0.01), respectively, among smokers with the CYP1A1 variant and GSTM1 null genotype groups. There was no statistically significant difference between the smoking and non-smoking groups with regard to the combination of the AhR and GSTM1 genotypes (data not shown). Among non-smokers, there was no correlation between any of the genotypes and adverse effects.
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Discussion |
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We have investigated the impact of maternal genetic polymorphisms, in particular those that are relevant to the metabolism of PAHs in tobacco smoke, on the association between maternal smoking during pregnancy and fetal growth. It has been reported that a subgroup of pregnant women with certain genotypes appears to be susceptible to the adverse effects of tobacco smoke, such as an increased risk of LBW, suggesting an interaction between metabolic genes and maternal smoking (Wang et al., 2002
; Nukui et al., 2004). Our present findings show that infant birth weight and length are significantly lower for mothers who were continuous smokers during pregnancy compared with non-smokers, after adjusting for the covariates. These results are consistent with previous studies, which also suggested that exposure to tobacco smoke in the third trimester has a greater adverse effect on fetal growth than exposure early in pregnancy (Lieberman et al., 1994; Cliver et al., 1995; Windham et al., 2000; England et al., 2001a, 2001b; Källén, 2001; Ohmi et al., 2002).
To the best of our knowledge, this is the first study to demonstrate that maternal smoking, in association with AhR, CYP1A1 and GSTM1 genotypes, might adversely affect both infant weight and length. Interindividual differences in metabolic activation and detoxification pathways are partly attributable to genetic polymorphisms associated with these enzymes. The CYP1A1 MspI variant genotype may increase enzyme activity. Moreover, GSTM1 detoxifies specific biologically active metabolites of PAHs, and carriers of the GSTM1 null genotype have a reduced ability to detoxify them. Activation of these pathways in the presence of compounds in tobacco smoke may be detrimental to birth outcomes. AhR regulates the induction of multiple metabolic enzymes, and this receptor is involved in the pathway that mediates the major toxic effects of xenobiotic chemicals. Genetic polymorphisms in AhR lead to substantial differences in sensitivity to the biochemical and toxic effects of chemical compounds in laboratory animals (Fernandez-Salguero et al., 1996; Thurmond et al., 1999; Shimizu et al., 2000). In human population studies, induced CYP1A1 activity was higher in lymphocytes from heterozygous or variant homozygous genotypes (Arg554/Lys554 or Lys554/Lys554) than in wild homozygous genotypes (Arg554/Arg554) (Wong et al., 2001a; Harper et al., 2002). Polymorphism in codon 554 has not been associated with the level of CYP1A1 mRNA or protein in lung tissues among Japanese smokers (Kawajiri et al., 1995). Our study shows that infants born to continuous smoking mothers having the AhR wild genotype had significantly lower estimated birth weight and length compared with non-smokers; moreover, smokers who had the AhR wild type and CYP1A1 variant genotype had the greatest reduction in both birth weight and length. Since there have been only a few epidemiological studies that included the association between AhR polymorphisms and human susceptibility to carcinogenesis (Kawajiri et al., 1995; Cauchi et al., 2001), further study is required to clarify the role of the Arg554Lys polymorphism in fetal development.
This study has the advantage of being the first to investigate how genetic susceptibility modulates risk of adverse birth outcomes from tobacco smoke exposure during pregnancy in Japanese subjects. Previous results in some studies that conflict with our data could be due to differences between genetically heterogeneous study populations (e.g. differences in ethnicity). In studies of United States populations, one study observed an association between the CYP1A1 genotype and risk of LBW (Wang et al., 2002), whereas another study did not detect an association between this genotype and adverse birth outcomes (Nukui et al., 2004). The latter study demonstrated that this difference could be attributed to the diverse ethnic compositions of the two study populations, resulting in different distributions of CYP1A1 allelic frequencies. The respective proportions of African-Americans and Caucasians in those two studies were 49.1% and 16.5% (Wang et al., 2002) versus 30.1% and 69.1% (Nukui et al., 2004).
Our present results do not show a statistically significant association between infant birth size and maternal smoking as linked to the GSTT1 genotype. This might be due to a relatively high frequency of the GSTT1 null genotype in Japanese populations (45.8%–52.0%) versus Caucasians (18.5%–24.8%) (Inoue et al., 2001; Murata et al., 2001; Stücker et al., 2002; Munaka et al., 2003; Sata et al., 2003; Nukui et al., 2004; Schneider et al., 2004; Komiya et al., 2005; Kurahashi et al., 2005; Ma et al., 2005).
Fetal toxicity from PAHs may be caused by DNA damage resulting from the activation of metabolites or the lack of detoxification of reactive intermediates as well as binding to receptors for placental growth factors, resulting in decreased exchange of oxygen and nutrients, or direct effects of carbon monoxide (Perera et al., 2004). A previous study reported that PAH–DNA adducts were elevated in both placental tissue and leukocytes of infants having the CYP1A1 variant genotype compared with infants having the CYP1A1 wild type genotype, whereas maternal adduct levels in leukocytes were not associated with either the CYP1A1 or GSTM1 genotypes. The different relationship between the CYP1A1 genotype and PAH–DNA adduct levels in the women and the infants may be due in part to reduced detoxification capabilities of GSTM1 in fetal tissues, where this enzyme is expressed rarely and only at low levels, thus rendering the fetus more susceptible to the effect of the CYP1A1 variant genotype (Whyatt et al., 1998). Nevertheless, the present study shows an association between maternal genotypes and adverse birth outcomes, suggesting transplacental transfer of PAH metabolites that were chemically modified by maternal gene polymorphisms associated with their encoded enzyme activity.
The participation rate was low in the present study. It was possible that women who take an interest in smoking cessation or toxicity of smoking would participate in our study more frequently. In our questionnaire survey, however, we did not inform the women that smoking was harmful to health and there was no intervention for smoking cessation. The prevalence of smoking during pregnancy in this study was similar to that of Sapporo City (18.7%) (Citizens Survey on Maternal and Child Health, 2001). Since the genotype distribution and allele frequencies in this study subjects were consistent with previous studies (Nakachi et al., 1993; Kawajiri et al., 1995; Kihara et al., 1995, 1999; Inoue et al., 2001; Murata et al., 2001; Munaka et al., 2003; Sata et al., 2003; Saijo et al., 2004; Komiya et al., 2005; Kurahashi et al., 2005; Ma et al., 2005), our participants seemed to be representatives of the general Japanese population. However, the low participation rate may cause possible selection bias and limited generalization of study findings should be made. Further prospective studies should be performed to confirm our preliminary findings.
The interpretation of our results is limited by the following points: the evaluation of the interaction between the maternal genotypes and smoking status was limited by the moderate sample sizes for some subgroups; the multiple linear regression analyses may have been affected by possible uncontrolled or inadequately controlled confounding variables, such as nutritional status during pregnancy; the evaluation of exposure to tobacco smoke was indirect, and thus there is a possibility of reporting bias; the relatively low frequencies of LBW and SGA may reinforce concerns about the limited generalizability of the enrolled study population.
The following points should be addressed in future studies to determine the genetic components (both maternal and fetal) underlying susceptibility to tobacco smoke with regard to adverse birth outcomes: an investigation of other genetic polymorphisms involved either in the metabolic activation or detoxification of tobacco smoke chemicals such as nicotine and N-nitrosamines; an examination of fetal genotypes to determine maternal–fetal gene interactions that may modulate the effect of maternal smoking during pregnancy.
In conclusion, the present study suggests an important modulating role for genetic polymorphisms in the PAH-metabolizing enzymes, AhR, CYP1A1 and GSTM1 (and combinations thereof), in the adverse effects of maternal smoking on infant birth size among Japanese subjects.
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Acknowledgements |
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We gratefully acknowledge the contribution of Dr N. Kanagami. We also thank F. Amano, Y. Nishiwaki and S. Nishiyama for recruitment of subjects and collection of maternal blood samples. 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 December 1, 2005; resubmitted on December 21, 2005; accepted on January 1, 2006.
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