Skip Navigation


American Journal of Epidemiology Advance Access originally published online on May 25, 2007
American Journal of Epidemiology 2007 166(3):313-322; doi:10.1093/aje/kwm090
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
166/3/313    most recent
kwm090v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Wu, T.
Right arrow Articles by Chen, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wu, T.
Right arrow Articles by Chen, D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Passive Smoking, Metabolic Gene Polymorphisms, and Infant Birth Weight in a Prospective Cohort Study of Chinese Women

Ting Wu1, Yonghua Hu1, Changzhong Chen2, Fan Yang3, Zhiping Li3, Zhian Fang3, Lihua Wang1 and Dafang Chen1

1 Department of Epidemiology and Biostatistics, Peking University Health Science Center, Beijing, China
2 Brigham and Women's Hospital, Harvard Medical School, Boston, MA
3 Anhui Biomedical Institute, Anqing, Anhui Province, China

Correspondence to Dr. Yonghua Hu or Dr. Dafang Chen, Department of Epidemiology and Biostatistics, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100083, People's Republic of China (e-mail: dafangchen{at}bjmu.edu.cn or yhhu{at}bjmu.edu.cn).

Received for publication September 18, 2006. Accepted for publication February 9, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The authors investigated whether polymorphisms in two maternal metabolic genes, cytochrome P-450 1A1 (CYP1A1) MspI and epoxide hydrolase 1 (EPHX1) Tyr113His, affect the association of maternal passive smoking with infant birth weight. The study was conducted in a cohort of 1,388 newly married mothers of liveborn singletons who worked in textile mills in Anqing, China, from 1996 to 2000. Multiple linear regression models were used to estimate the associations of passive smoking and genetic susceptibility with birth weight, with adjustment for important potential confounders. In the passive smoking group, there was a remarkable decrease in birth weight with the C/C6235 genotype (156.3 g, 95% confidence interval (CI): –283.6, –29.0) for CYP1A1 MspI and with Tyr/His113 (93.8 g, 95% CI: –188.6, –1.1) as compared with His/His113 (244.6 g, 95% CI: –491.0, –1.9) for EPHX1. When results were stratified by maternal genotype, passive smoking conferred a significantly negative effect in the EPHX1 Tyr/His113 group (103.5 g, 95% CI: –205.8, –9.2) and in the His/His113 group (687.3 g, 95% CI: –748.3, –178.3). The data further showed that there was a significant interaction between maternal passive smoking and maternal EPHX1 genotype for birth weight. The authors conclude that the CYP1A1 MspI and EPHX1 genotypes modified the association between maternal passive smoking and infant birth weight in this study, which is suggestive of possible gene-environment interaction.

birth weight; cytochrome P-450 CYP1A1; epoxide hydrolases; infant; polymorphism, genetic; tobacco smoke pollution

Abbreviations: CI, confidence interval; CYP1A1, cytochrome P-450 1A1; EPHX1, epoxide hydrolase 1; PCR, polymerase chain reaction


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Low birth weight (<2,500 g) is a powerful predictor of infant survival and childhood morbidity, as well as adulthood health conditions (1, 2). The etiology of low birth weight remains unclear, but both environmental and genetic factors may play important roles (3). These factors may include cigarette smoking (4, 5), caffeine consumption (6), exposure to pesticides, organic solvents, and related compounds (7, 8), infant sex, prenatal maternal mood (9), and strong familial aggregation (3). Exposure to cigarette smoke during pregnancy, via active or passive routes, is known to be a strong risk factor for preterm birth and low birth weight (10–15). However, not all women who have been passively exposed to cigarettes during pregnancy have infants with reduced birth weight. This variability may be related to genetic susceptibility.

Cigarette smoke constituents, including mutagenic, neurotoxic, and fetotoxic agents, can pass through the placenta even in the early stages of pregnancy and are detected in the urine of newborns (4, 5). A person's ability to convert toxic metabolites of cigarette smoke to less harmful moieties is critical for minimizing their adverse health effects. Aryl hydrocarbon hydroxylase, encoded by the cytochrome P-450 1A1 (CYP1A1) gene, is a well-studied phase I enzyme and is particularly relevant to the metabolism of chemicals in cigarette smoke. Detoxification of these epoxides may occur through conjugation with certain endogenous functional groups such as glutathione, catalyzed by glutathione S-transferases (16), or by hydration, catalyzed by epoxide hydrolases in phase II. The end product becomes a stable hydrophilic compound that can easily be excreted (17). The microsomal form of epoxide hydrolase, epoxide hydrolase 1 (EPHX1), which is encoded by the EPHX1 gene, catalyzes the conversion of a broad spectrum of highly reactive aliphatic epoxides to less toxic trans-dihydrodiols (18). Both the CYP1A1 gene and the EPHX1 gene are highly polymorphic in the population (19, 20), and their polymorphisms have been associated with their encoded enzyme activities. CYP1A1 MspI variance may increase aryl hydrocarbon hydroxylase activity, and EPHX1 Tyr113His variance may decrease EPHX 1 activity (21, 22). Interindividual differences in susceptibility to the adverse health effects of cigarette smoke are partly attributable to different maternal genotypes associated with these enzymes.

Previous studies have shown that maternal genotype can modify the association between maternal cigarette smoking and infant birth weight (23, 24), and 70 percent of nonsmoking Chinese women between the ages of 20 and 50 years have reported passive exposure to cigarette smoke (25). It is important to elucidate the effects of passive smoking on pregnancy outcomes; even if the magnitudes of effect are modest, the adverse impacts on the public's health will be widespread with so prevalent an exposure. In this study, we used CYP1A1 MspI and EPHX1 Tyr113His gene polymorphisms to characterize genetic susceptibility to low birth weight and to assess the interaction between metabolic genes and passive cigarette smoking.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study site and population
This analysis was part of a prospective reproductive health study carried out from 1996 to 2000 among female textile workers in Anqing, China, an urban area approximately 200 km west of Shanghai. All employees of the textile mills received health care, including prenatal care, delivery, and postnatal care, at Anqing Hospital. To be eligible for inclusion during field enrollment, an employee had to be 1) working full-time, 2) newly married, and 3) aged 20–34 years and 4) had to have obtained permission to have a child. All of the women were nulliparous. Women were excluded if 1) they were already pregnant before enrollment; 2) they had tried unsuccessfully to get pregnant for at least 1 year at any time in the past; or 3) they were planning to quit, change jobs, or move out of the city over the 1-year course of follow up. The study protocols were approved by the Human Subject Committee of Beijing Medical University. We obtained written informed consent from each woman.

Data collection procedures
We used the Chinese marriage registration system to identify newlywed couples and those planning a first pregnancy. Upon enrollment, a physical examination was performed, and height and weight were measured according to a standard protocol. At enrollment, a structured baseline questionnaire was administered by a trained interviewer to the women and their husbands in order to collect information on occupational exposures, personal habits such as cigarette smoking and alcohol consumption, living environment, passive exposure to cigarette smoke, dietary intake, menstrual and reproductive history, and contraceptive use. When a woman decided to stop contraception in order to become pregnant, she began keeping a daily diary on menstrual bleeding and associated symptoms and exposure to tobacco smoke and other occupational exposures. If a woman reported a missed or late menstrual period or had early signs or symptoms of pregnancy, she was instructed to go to Anqing Hospital for a check-up and to give a urine sample for pregnancy testing. Once a woman was confirmed to be pregnant, collection of the daily diaries was terminated and the woman received regular prenatal care and delivery services at the designated hospital according to standard clinical guidelines. The woman was followed up with regard to pregnancy outcomes, including infant birth weight, gestational age, and infant sex, by the research staff. In this study, infant birth weight was measured in the delivery room by a trained nurse and was accurate to 1 g. Blood samples were obtained from women via venipuncture by a skilled phlebotomist. The genomic DNA was extracted according to a standard protocol (26).

Assessment of environmental tobacco smoke
There is evidence showing that cotinine level is quite positively related to self-reported passive smoke exposure (27, 28). Therefore, in this study, information on passive smoking during the index pregnancy was based on women's self-reporting and was obtained for three time periods: the first, second, and third trimesters. Each woman recorded the mean number of cigarettes smoked per day at home by regular household members during the three time periods. In our study, the specific question on the questionnaire was, "On average, what is the number of cigarettes someone smoked indoors at home per day while you were exposed in the last 3 months?" Exposure to tobacco smoke at the workplace was not considered, because none of the employees at the textile mills were allowed to smoke at work. In the subsequent analysis, maternal passive smoking at home was considered as both a binary variable and a continuous variable. We defined "non-passive smoking" as no smoking by regular household members at home during any of the three time periods of pregnancy and "passive smoking" as any smoking by regular household members at home during any of the three time periods. We calculated the average number of cigarettes smoked per day at home during the three time periods.

Genotyping methods
Detection of the CYP1A1 MspI polymorphism
For detection of the CYP1A1 MspI polymorphism, the primers used in the polymerase chain reaction (PCR) were bases 42–65 (5'-TCACTCGTCTAAATACTCACCCTG-3') and the segment from base pair 435 to base pair 455 (5'-TAGGAGTCTTGTCTCATGCCT-3'). A 20-ng DNA sample was used in a 10-µl PCR reaction containing 50 mM potassium chloride, 1.5 mM magnesium chloride, 10 mM Tris-hydrochloric acid, 0.1 percent Triton X-100, 200 µM deoxyribonucleoside triphosphates, 200 nM primers, and 0.25 U Taq polymerase. The PCR amplification was carried out under the following conditions: 94°C for 3 minutes, followed by 35 cycles of 94°C for 30 seconds, 54°C for 45 seconds, and 72°C for 45 seconds, followed by a final extension at 72°C for 7 minutes. The reaction products were subjected to digestion by MspI for 15 hours at 37°C. This process results in 295-, 160-, and 135-base-pair products and is able to detect all three possible genotypes for the polymorphism: T/T6235 (homozygous wild type), T/C6235 (heterozygous variant type), and C/C6235 (homozygous variant type).

Detection of the EPHX1 Tyr113His polymorphism
We examined the EPHX1 Tyr113His polymorphism at position 113 in exon 3 of the EPHX1 gene. We used the primers 5'-GGCTTCAACTCCAACTACCTG-3' and 5'-CAATCTTAGTCTTGAAGTGACGGT-3' in the PCR. A 20-ng DNA sample was used in a 10-µl PCR reaction containing 50 mM potassium chloride, 1.5 mM magnesium chloride, 10 mM Tris-hydrochloric acid, 0.1 percent Triton X-100, 200 µM deoxyribonucleoside triphosphates, 200 nM primers, and 0.25 U Taq polymerase. The PCR amplification was carried out at 94°C for 3 minutes, followed by 35 cycles of 94°C for 30 seconds, 54°C for 45 seconds, and 72°C for 45 seconds, followed by a final extension at 72°C for 7 minutes. The products of 112 base pairs were digested with T th111 I for 15 hours at 37°C. Persons with the homozygous wild genotype show 30- and 90-base-pair fragments, while heterozygous persons show three bands at 30, 90, and 120 base pairs, respectively. Persons with the homozygous variant genotype show only a 120-base-pair band.

Previously sequenced genomic DNA samples were used as positive controls for the homozygous wild, heterozygous, and homozygous mutant genotypes with every PCR analysis to verify the reproducibility of the restriction fragment length polymorphism PCR and to confirm the accuracy of genotype classification. Approximately 10 percent of the samples were randomly selected for reanalysis for verification of the results of the genotyping assays.

Statistical methods
Considering the low number of low birth weight infants (6.5 percent for the nonexposed group and 9.6 percent for the exposed group) and to preserve statistical power, we analyzed our data using birth weight as a continuous variable. We first examined the association between maternal genotype and infant birth weight without consideration of passive cigarette smoking, using multiple linear regression modeling with adjustment for major covariates. We then investigated whether the association between passive smoking and reduced birth weight was modified by maternal genotype, by estimating the association between passive smoking and birth weight in total samples as well as in subgroups stratified by the specific maternal genotypes. To further assess gene-environment interaction, we examined the combined association of passive smoking and maternal genotype with birth weight in six subgroups defined by passive smoking status (no, yes) and maternal genotype for CYP1A1 MspI (T/T6235, T/C6235, and C/C6235) and EPHX1 (Tyr/Tyr113, Tyr/His113, and His/His113). Finally, we tested for gene-environment interaction by adding a product term in the regression model. In all analyses, results were adjusted for the following important potential confounders: maternal age (<25, 25–27, and ≥28 years), education (elementary school, middle school, and high school or above), shift work (no, yes), exposure to noise at work (no, yes), exposure to vibration at work (no, yes), whether the job was perceived to be stressful (no, yes), prepregnancy height and weight, average number of cooking days per week (days on which the woman cooked for her family; <1, 1–2, 3–5, and 6–7 days/week), history of pregnancy (prior miscarriage or abortion; no, yes), and infant sex. All p values were two-sided, and statistical significance was defined as p = 0.05. Selection of the covariates was based on the current literature on passive smoking and the standard statistical procedures for variable selection (23, 24). We use SAS software (SAS Institute Inc., Cary, North Carolina) for all analyses. The frequencies of the T alleles of CYP1A1 MspI and the C alleles of EPHX1 Tyr113His in these populations conformed to Hardy-Weinberg equilibrium.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
A total of 1,540 mothers were invited to participate in this study. Of those, 152 mothers were excluded because of failure in extracting DNA, failure of genotyping, or missing data. The final analysis included 1,388 mothers (680 non-passive smokers and 708 passive smokers) who gave birth to live singletons at the Anqing Hospital. As table 1 shows, the nonexposed and exposed groups were similar in terms of age distribution, maternal prepregnancy weight, shift work, exposure to noise and toxins, perceived stress, cooking, and infant sex, whereas the two groups differed with regard to maternal prepregnancy height, education, exposure to vibration in the current job, and history of pregnancy. The mean birth weight was 30.5 g lower (p = 0.2317) for the exposed group than for the nonexposed group, but there was no significant difference. The mean gestational age was 39.5 weeks for both the exposed group and the nonexposed group.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Characteristics of female textile mill workers and their newborn infants according to passive exposure to cigarette smoke at home during pregnancy, Anqing, China, 1996–2000

 
Table 2 presents mean values and standard deviations for the total sample and for subgroups defined by maternal passive smoking status. In addition, table 2 shows the adjusted association between maternal genotype and infant birth weight, where ß represents the difference in mean birth weight between the variant-type group and the homozygous wild-type group after adjustment for the covariates listed. For CYP1A1 MspI genotypes, without consideration of passive smoking status, there was no significant effect of the T/C6235 or C/C6235 genotype on infant birth weight in comparison with the T/T6235 genotype (table 2). When maternal passive smoking was considered, the association between genotype and birth weight varied remarkably by passive smoking status. In the passive smoking group, a significant decrease in mean birth weight (156.3 g, 95 percent confidence interval (CI): –283.6, –29.0) was observed among mothers with the C/C6235 genotype as compared with those with the T/T6235 genotype. However, a different pattern emerged for EPHX1. Without consideration of passive smoking status, the mean birth weight was associated with genotype; that is, compared with Tyr/Tyr113 mothers, infant birth weight was reduced by 60.0 g (95 percent CI: –119.7, –0.3) and 167.9 g (95 percent CI: –329.6, –6.1) among Tyr/His113 and His/His113 mothers, respectively; in the presence of passive smoking, infant birth weight was reduced by 93.8 g (95 percent CI: –188.6, –1.1) in Tyr/His113 mothers and 244.6 g (95 percent CI: –491.0, –1.9) in His/His113 mothers.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Effect of maternal cytochrome P-450 (CYP1A1) MspI and epoxide hydrolase 1 (EPHX1) Tyr113His genotypes* on infant birth weight, in total and by passive exposure to cigarette smoke at home during pregnancy, Anqing, China, 1996–2000

 
Table 3 presents mean values and standard deviations for the total sample and for subgroups defined by maternal genotype. In addition, table 3 shows the adjusted association between maternal passive smoking and infant birth weight. As estimated from the multiple linear regression model, passive smoking was not remarkably associated with a reduction in mean birth weight of 17.2 g (95 percent CI: –65.0, 30.6) in the total sample. There was also no significant association of passive smoking with infant birth weight with stratification by CYP1A1 MspI genotype. However, this association differed by maternal genotype for EPHX1 Tyr113His. Passive smoking did not confer any adverse effect in the Tyr/Tyr113 group but had a significantly negative effect in the Tyr/His113 group (–103.5 g, 95 percent CI: –205.8, –9.2) and in the His/His113 group (–687.3 g, 95 percent CI: –748.3, –178.3). In other words, for EPHX1 Tyr113His, the negative effects of maternal passive smoking on infant birth weight depended on maternal genotype.


View this table:
[in this window]
[in a new window]

  		TABLE 3. Mean infant birth weight according to maternal passive smoking at home during pregnancy and adjusted association between passive smoking and infant birth weight, in total and by maternal cytochrome P-450 (CYP1A1) MspI and epoxide hydrolase 1 (EPHX1) genotype,* Anqing, China, 1996–2000

 
We further assessed the association of amount of passive smoking with infant birth weight by considering passive smoking as a continuous variable (table 4). For every cigarette a mother was passively exposed to, mean birth weight decreased 18.0 g (95 percent CI: –30.2, –5.9) in the CYP1A1 MspI C/C6235 group and 10.4 g (95 percent CI: –19.8, –1.1) and 346.2 g (95 percent CI: –459.2, –15.2) in the EPHX1 Tyr/His113 and His/His113 groups, respectively.


View this table:
[in this window]
[in a new window]

  		TABLE 4. Adjusted association of amount of passive smoking during pregnancy with infant birth weight, in total and by maternal cytochrome P-450 (CYP1A1) MspI and epoxide hydrolase 1 (EPHX1) genotype,* Anqing, China, 1996–2000

 
Table 5 presents data on the combined association of passive smoking and maternal genotype with infant birth weight, where ß represents the difference in mean birth weight between each subgroup and the reference group. In the absence of passive smoking, maternal genotype alone did not confer any significant adverse effect for either CYP1A1 MspI or EPHX1 Tyr113His. However, in the presence of maternal passive smoking, remarkable reductions in mean birth weight of 112.1 g (95 percent CI: –179.3, –12.2) and 315.6 g (95 percent CI: –506.2, –87.1) were found in the EPHX1 Tyr/His113 group and the His/His113 group, respectively. A test of interaction between maternal passive smoking and maternal EPHX1 Tyr113His genotype was statistically significant for birth weight.


View this table:
[in this window]
[in a new window]

  		TABLE 5. Combined associations of passive smoking during pregnancy and maternal cytochrome P-450 (CYP1A1) MspI and epoxide hydrolase 1 (EPHX1) genotype with infant birth weight, Anqing, China, 1996–2000

 
We also analyzed the combined association of passive smoking amount and maternal genotype with infant birth weight, as well as the association with infant birth weight when both CYP1A1 MspI and EPHX1 Tyr113His were considered simultaneously in the presence or absence of passive smoking. However, there was no significant interaction (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Our study showed that the association of maternal CYP1A1 MspI and EPHX1 Tyr113His genotypes with birth weight emerged only in those mothers who were passively exposed to environmental tobacco smoke. More importantly, the study provided consistent evidence that the adverse effects of maternal passive smoking on infant birth weight were modified by maternal CYP1A1 MspI and EPHX1 Tyr113His genotypes. Our data demonstrated that a subgroup of pregnant women with certain genotypes appeared to be particularly susceptible to the adverse effect of passive cigarette smoking, suggesting an interaction between metabolic genes and passive smoking.

Although there are few published data on genetic susceptibility to maternal passive cigarette smoking in relation to birth weight, this susceptibility is biologically plausible. Persons exposed to environmental tobacco smoke are subjected to most of the same constituents as those contained in mainstream smoke, but the pattern and amounts of exposure differ (29). The potential passive smoke mechanisms are essentially the same as those for active smoking (12, 30), including vasocontriction and reduced placental blood flow due to nicotine (10), maternal and fetal hypoxia due to carboxyhemoglobin formation, and genotoxicity; that is, reduction of birth weight caused by fetal growth retardation may also be due to disturbance of cell regulation caused by DNA adducts and damage (31). There is evidence suggesting that toxicity is produced by one or more metabolites of cigarette smoke, particularly the covalent binding to cellular macromolecules, especially DNA (32, 33). DNA damage may result from some cytochrome P-450 variants (34) and the lack of detoxification of reactive tobacco smoke intermediates. Further studies (35, 36) demonstrated that levels of benzo(a)pyrene diol-epoxide–DNA adducts and bulky DNA adducts were significantly and positively correlated with CYP1A1 enzyme activity. Moreover, the microsomal form of epoxide hydrolase, EPHX1, which is encoded by the EPHX1 gene, catalyzes the conversion of a broad spectrum of highly reactive aliphatic epoxides to less toxic trans-dihydrodiols (18). Thus, a person's ability to convert toxic metabolites of cigarette smoke to less harmful moieties is important for minimizing the toxic effect on birth outcomes. CYP1A1 MspI variant genotypes may increase enzyme activity (37), while the substitution of histidine for the more common tyrosine at codon 113 in exon 3 of EPHX1 may lead to a decrease in enzyme activity (22). Consistently, our study found that the passively smoking mothers who had the CYP1A1 MspI variant genotype C/C6235 or the EPHX1 Tyr113His variant genotype Tyr/His113 or His/His113, which reduces a person's ability to convert toxic metabolites of cigarette smoke to less harmful hydrophilic compounds, had infants with significantly lower birth weights than the reference groups. Furthermore, the greater the amount of passive smoking to which the pregnant women were exposed, the more remarkably birth weight was reduced in the C/C6235 group of CYP1A1 MspI and the His/His113 group of EPHX1, suggesting a dose-response relation between passive smoking and infant birth weight.

Several methodological limitations should be considered when interpreting our results. Maternal passive smoking was based on self-reports rather than objective measurements and thus may have been subject to reporting bias and misclassification, which may have caused underreporting of smoking status and underestimation of the effect of passive smoking. Second, we adjusted for several variables, including demographic characteristics, occupational exposure, and reproductive history, in the regression analyses. However, we cannot exclude the possibility of confounding by uncontrolled or inadequately controlled risk factors. For example, we made no attempt to assess nutritional status and maternal weight gain during pregnancy, and socioeconomic status was not considered in our study. Third, the association between genetic susceptibility to passive smoking and reduced birth weight found in this study may be causal or may be a marker for other polymorphisms which are the true susceptibility loci or biologic pathways, because of the possibility of linkage disequilibrium. For example, the EPHX1 His139Arg polymorphism, substitution of arginine for histidine at codon 139 in exon 4, which increases EPHX 1's enzymatic activity by 25 percent, could modify the effect of the loss-of-function variant Tyr113His with respect to low birth weight (38). In addition, the Ile462Val polymorphism in exon 7 of CYP1A1 is usually linked with MspI and may increase the activity of aryl hydrocarbon hydroxylase, and is particularly relevant to the metabolism of chemicals in cigarette smoke. Fourth, there may be potential interactions with polymorphisms in genes for other phase II enzymes such as glutathione S-transferase T1 (GSTT1) and glutathione S-transferase M1 (GSTM1), which are also reported to be associated with a lack of or reduction in enzymatic activity toward several substrates, including those found in tobacco smoke (39–42), and which may modify the effects of CYP1A1 MspI and EPHX1 Tyr113His to some extent. Extensive efforts should be made to examine other polymorphisms to develop haplotype studies and to further test for these interactions. In addition, we only examined maternal genotypes, and the roles of fetal genotypes in modifying the adverse effects of passive smoking and maternal-fetal gene interaction remain to be determined.

In conclusion, we have demonstrated that the association between maternal passive smoking and reduced infant birth weight is significantly modified by maternal genotype. This study provides evidence of gene-environment interaction and suggests the importance of further assessing the role of genetic susceptibility in the evaluation of reproductive toxins. A coherent gene-environment interaction approach may help to identify high-risk subpopulations for clinical or public health interventions.


   ACKNOWLEDGMENTS
 
This study was supported in part by grant HD32505 from the US National Institute of Child Health and Human Development; grants ES8337, ES-00002, ES06198, ES11682, and ES08957 from the US National Institute of Environmental Health Sciences; and grants 20-FY98-0701 and 20-FY02-56 from the March of Dimes Birth Defects Foundation, as well as the doctoral research foundation of the Ministry of Education, People's Republic of China.

The authors gratefully acknowledge the assistance and cooperation of the staff of the Anhui Biomedical Institute.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Epstein MF. Major causes of neonatal mortality and morbidity. In: Follow-up management of the high-risk infant—Taeusch HW, Yogman MW, eds. (1987) Boston, MA: Little, Brown and Company. 15–20.
  2. Wilcox AJ. On the importance—and the unimportance—of birthweight. Int J Epidemiol (2001) 30:1233–41.[Abstract/Free Full Text]
  3. Wang X, Zuckerman B, Coffman GA, et al. Familial aggregation of low birth weight among whites and blacks in the United States. N Engl J Med (1995) 333:1744–9.[Abstract/Free Full Text]
  4. Kline J, Stein ZA, Susser M, et al. Smoking: a risk factor for spontaneous abortion. N Engl J Med (1977) 297:793–6.[Abstract]
  5. Windham GC, Swan SH, Fenster L. Parental cigarette smoking and the risk of spontaneous abortion. Am J Epidemiol (1992) 135:1394–403.[Abstract/Free Full Text]
  6. Dlugosz L, Belanger K, Hellenbrand K, et al. Maternal caffeine consumption and spontaneous abortion: a prospective cohort study. Epidemiology (1996) 7:250–5.[Web of Science][Medline]
  7. Savitz DA, Whelan EA, Kleckner RC. Effect of parents' occupational exposures on risk of stillbirth, preterm delivery, and small-for-gestational-age infants. Am J Epidemiol (1989) 129:1201–18.[Abstract/Free Full Text]
  8. Lindbohm ML. Effects of parental exposure to solvents on pregnancy outcome. J Occup Environ Med (1995) 37:908–14.[Web of Science][Medline]
  9. Misri S, Oberlander TF, Fairbrother N, et al. Relation between prenatal maternal mood and anxiety and neonatal health. Can J Psychiatry (2004) 49:684–9.[Medline]
  10. Jaakkola JJ, Jaakkola N, Zahlsen K. Fetal growth and length of gestation in relation to prenatal exposure to environmental tobacco smoke assessed by hair nicotine concentration. Environ Health Perspect (2001) 109:557–61.[Web of Science][Medline]
  11. Frisbie WP, Biegler M, de Turk P, et al. Racial and ethnic differences in determinants of intrauterine growth retardation and other compromised birth outcomes. Am J Public Health (1997) 87:1977–83.[Abstract/Free Full Text]
  12. Windham GC, Hopkins B, Fenster L, et al. Prenatal active or passive tobacco smoke exposure and the risk of preterm delivery or low birth weight. Epidemiology (2000) 11:427–33.[CrossRef][Web of Science][Medline]
  13. Ahluwalia IB, Grummer-Strawn L, Scanlon KS. Exposure to environmental tobacco smoke and birth outcome: increased effects on pregnant women aged 30 years or older. Am J Epidemiol (1997) 146:42–7.[Abstract/Free Full Text]
  14. Rubin DH, Krasilinkoff PA, Leventhal JM, et al. Effect of passive smoking on birth weight. Lancet (1986) 11:415–17.
  15. Haddow JE, Knight GJ, Palomaki GE, et al. Second-trimester serum cotinine levels in nonsmokers in relation to birth weight. Am J Obstet Gynecol (1988) 159:481–4.[Web of Science][Medline]
  16. Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol (1995) 30:445–600.[Web of Science][Medline]
  17. Seidegard J, Ekstrom G. The role of human glutathione transferases and epoxide hydrolases in the metabolism of xenobiotics. Environ Health Perspect (1997) 105(suppl 4):791–9.[CrossRef][Web of Science][Medline]
  18. Raaka S, Hassett C, Omiencinski CJ. Human microsomal epoxide hydrolase: 5'-flanking region genetic polymorphisms. Carcinogenesis (1998) 19:387–93.[Abstract/Free Full Text]
  19. Xu X, Kelsey KT, Wiencke JK, et al. Cytochrome P450 CYP1A1 MspI polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev (1996) 5:687–92.[Abstract/Free Full Text]
  20. Gaedigk A, Spielberg SP, Grant DM. Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions. Pharmacogenetics (1994) 4:142–53.[Web of Science][Medline]
  21. Kawajiri K, Nakachi K, Imai K, et al. Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P4501A1 gene. FEBS Lett (1990) 263:131–3.[CrossRef][Web of Science][Medline]
  22. Hassett C, Aicher L, Sidhu JS, et al. Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants. Hum Mol Genet (1994) 3:421–8.[Abstract/Free Full Text]
  23. Nukui T, Day RD, Sims CS, et al. Maternal/newborn GSTT1 null genotype contributes to risk of preterm, low birthweight infants. Pharmacogenetics (2004) 14:569–76.[CrossRef][Web of Science][Medline]
  24. Wang X, Zuckerman B, Pearson C, et al. Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA (2002) 287:195–202.[Abstract/Free Full Text]
  25. Yang G, Fan L, Tan J, et al. Smoking in China: findings of the 1996 National Prevalence Survey. JAMA (1999) 282:1247–53.[Abstract/Free Full Text]
  26. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. (1989) Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
  27. DeLorenze GN, Kharrazi M, Kaufman FL, et al. Exposure to environmental tobacco smoke in pregnant women: the association between self-report and serum cotinine. Environ Res (2002) 90:21–32.[Medline]
  28. Niu J, Hu J, Zhang L, et al. Detection and analysis of biomarker of pregnant woman subjected to passive smoking. (In Chinese). J Environ Health (2005) 22:109–10.
  29. Underwood PB, Kesler KF, O'Lane JM, et al. Parental smoking empirically related to pregnancy outcome. Obstet Gynecol (1967) 29:1–8.[Web of Science][Medline]
  30. Windham GC, Eaton A, Hopkins B. Evidence for an association between environmental tobacco smoke exposure and birthweight: a meta-analysis and new data. Paediatr Perinat Epidemiol (1999) 13:35–57.[CrossRef][Web of Science][Medline]
  31. Perera FP, Jedrychowski W, Rauh V, et al. Molecular epidemiologic research on the effects of environmental pollutants on the fetus. Environ Health Perspect (1999) 107(suppl 3):451–60.[Web of Science][Medline]
  32. National Research Council, National. Academy of Sciences. Polycyclic aromatic hydrocarbons: evaluation of sources and effects. (1983) Washington, DC: National Academy Press.
  33. Everson RB, Randerath E, Santella RM, et al. Quantitative associations between DNA damage in human placenta and maternal smoking and birth weight. J Natl Cancer Inst (1988) 80:567–76.[Free Full Text]
  34. Bartsch H, Nair U, Risch A, et al. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol Biomarkers Prev (2000) 9:3–28.[Abstract/Free Full Text]
  35. Alexandrov K, Rojas M, Geneste O, et al. An improved fluorometric assay for dosimetry of benzo(a)pyrene diol-epoxide–DNA adducts in smokers' lung: comparisons with total bulky adducts and aryl hydrocarbon hydroxylase activity. Cancer Res (1992) 52:6248–53.[Abstract/Free Full Text]
  36. Bartsch H, Rojas M, Alexandrov K, et al. Metabolic polymorphism affecting DNA binding and excretion of carcinogens in humans. Pharmacogenetics (1995) 5:S84–90. (spec no.)[CrossRef][Web of Science][Medline]
  37. Landi MT, Bertazzi PA, Shields PG, et al. Association between CYP1A1 genotype, mRNA expression and enzymatic activity in humans. Pharmacogenetics (1994) 4:242–6.[Web of Science][Medline]
  38. Saito S, Iida A, Sekine A, et al. Seventy genetic variations in human microsomal and soluble epoxide hydrolase genes in the Japanese population. J Hum Genet (2001) 46:325–9.[CrossRef][Web of Science][Medline]
  39. Strange RC, Jones PW, Fryer AA. Glutathione S-transferase: genetics and role in toxicology. Toxicol Lett (2000) 112-113:357–63.
  40. Ali-Osman F, Brunner JM, Kutluk TM, et al. Prognostic significance of glutathione S-transferase pi expression and subcellular localization in human gliomas. Clin Cancer Res (1997) 3:2253–61.[Abstract/Free Full Text]
  41. Armstrong RN. Glutathione S-transferases: reaction mechanism, structure, and function. Chem Res Toxicol (1991) 4:131–40.[CrossRef][Web of Science][Medline]
  42. Strange RC, Faulder CG, Davis BA, et al. The human glutathione S-transferases: studies on the tissue distribution and genetic variation of the GST1, GST2 and GST3 isozymes. Ann Hum Genet (1984) 48:11–20.[Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am J EpidemiolHome page
M. Gwinn, I. Guessous, and M. J. Khoury
Invited Commentary: Genes, Environment, and Hybrid Vigor
Am. J. Epidemiol., September 15, 2009; 170(6): 703 - 707.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
C. G. Julian, M. J. Wilson, M. Lopez, H. Yamashiro, W. Tellez, A. Rodriguez, A. W. Bigham, M. D. Shriver, C. Rodriguez, E. Vargas, et al.
Augmented uterine artery blood flow and oxygen delivery protect Andeans from altitude-associated reductions in fetal growth
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1564 - R1575.
[Abstract] [Full Text] [PDF]

Home page
 Mayo Clin Proc.Home page
T. Sher, G. K. Dy, and A. A. Adjei
Small Cell Lung Cancer
Mayo Clin. Proc., March 1, 2008; 83(3): 355 - 367.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
166/3/313    most recent
kwm090v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Wu, T.
Right arrow Articles by Chen, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wu, T.
Right arrow Articles by Chen, D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?