Grantee Research Project Results

2000 Progress Report: Genetic Susceptibility to the Effects of Aromatic Solvents on Reproductive Health

EPA Grant Number: R825818
Title: Genetic Susceptibility to the Effects of Aromatic Solvents on Reproductive Health
Investigators: Xu, Xiping , Ryan, Louise , Chen, Dafang , Christiani, David , Wang, Lihua , Smith, Thomas
Institution: Harvard University
EPA Project Officer: Aja, Hayley
Project Period: February 1, 1998 through January 31, 2001
Project Period Covered by this Report: February 1, 1999 through January 31, 2000
Project Amount: $792,308
RFA: Issues in Human Health Risk Assessment (1997) RFA Text | Recipients Lists
Research Category: Human Health

Objective:

The objective of the research is to assess the impact of gene-aromatic solvent interaction on adverse reproductive outcomes, including menstrual disturbance, infertility, spontaneous abortion, preterm delivery, and low birth weight. Specifically, using resources from a large, well-characterized cohort study, we will prospectively investigate whether the risk of adverse reproductive outcomes associated with aromatic solvent exposure is elevated in individuals with relevant variants of one of the following nine genes: GSTM1, GSTT1, CYP1A1, CYP2D6, CYP2E1, NAT2, NQO1, ALDH2, and EPHX.

Progress Summary:

To examine the genetic influence on preterm delivery, we have devised a study to evaluate the major candidate genes of preterm delivery and to test gene-environment interactions. Our study includes 500 existent preterm trios including 500 preterm babies and their parents and 500 maternal age matched term controls collected in China. We will perform the transmission/disequilibrium test (TDT) on candidate genes thought to be important in each of the four biological pathways of PTD: (1) decidual chorioamniotic inflammation: interleukin1 (IL-1), IL-6, and tumor necrosis factor (TNF); (2) maternal and fetal stress: corticotropin-releasing hormone (CRH); (3) uteroplacenta vasculopathy: methylenetereahydrofolate reductase (MTHFR); and (4) susceptibility to environmental toxins: GSTM1, GSTT1, GYP1A1, CYP2D6, CYP2E1, NAT2, NQO1, ALDH2, and EPHX. We also will perform more standard case-control analyses on the 500 preterm cases and 500 term controls to examine gene-environment interactions. The major environmental, nutritional, and social factors as well as clinical variables known or suspected to be associated with PTD will be used to test for gene-environment interactions. This study integrates epidemiologic and clinical data as well as genetic markers along major pathogenic pathways of PTD. The findings from this study should improve our understanding on genetic influence on PTD and potential gene-environment interactions.

In another project, investigators assessed whether the association between maternal cigarette smoking and infant birthweight is modified by two maternal genes?CYP1A1 and GSTT1?that encode cytochrome P-450 and glutathione-transferase metabolic enzymes, respectively. A total of 740 mothers (173 smokers and 567 nonsmokers) who delivered singleton live births were studied. Smoking and other epidemiologic data were obtained by questionnaire interview. CYP1A1 and GSTT1 genotypes were determined for all mothers. Without consideration of genotype, continuous maternal smoking was associated with a 360 g (se = 91) reduction in birthweight. When stratified by CYP1A1 genotype, the estimated reduction in birthweight associated with continuous maternal smoking was 215 g (se = 119) for the AA group, but was 565 g (se = 147) for the Aa/aa group. When stratified by GSTT1 genotype, the estimated reduction in birthweight was 266 g (se = 107) for the present group, but was 659 g (se = 187) for the absent group. When both CYP1A1 and GSTT1 were considered, the greatest reduction in birthweight was found among smoking mothers with CYP1A1 Aa/aaCGSTT1 absent genotypes (1278 g, se = 235). Among non-smoking mothers, genotype alone did not confer an adverse effect. A similar pattern was found for the risk of low birthweight and preterm delivery.

Few published studies have examined the role of genetic factors and gene-environment interactions in relation to preterm delivery. We assessed maternal and fetal CYP1A1 HincII genotypes and benzene exposure in relation to gestational age among 502 mother-infant pairs (277 unexposed and 225 exposed) in Beijing, China. We used two complementary analytical approaches: Transmission Disequilibrium Test when only one parent is available (1-TDT) and mixed effects model, with adjustment for maternal age, passive smoking, pre-pregnancy weight and height, and infant gender. We also extended 1-TDT to use the log-linear analysis to test gene-environment interaction. The 1-TDT did not detect an excess transmission of CYP1A1 alleles among mothers with reduced (<40 weeks) gestational age (p = 0.83 and 0.16, for benzene exposed and unexposed, respectively) compared to mothers without, and the log-linear analysis did not detect an interaction between the CYP1A1 gene and the benzene exposure. Using the mixed effects model, we found that the fetal AA-maternal AA genotype combination was associated with a significant reduction in gestational age in the benzene-exposed group (b = -0.280.14, p<0.05). A linear regression-based test of gene-benzene interaction also was highly significant (b = -0.660.22, p<0.005). In conclusion, consistent with our earlier report, our data suggest that CYP1A1 genotype alone is not associated with gestational age. However, CYP1A1 gene polymorphisms significantly modified the association between benzene exposure and gestational age (i.e., there is a gene-benzene interaction). Our study underscores the importance of further assessing the role of both maternal and fetal genetic susceptibility in the evaluation of reproductive toxins.

Future Activities:

During the coming year, we will further assess the role of genetic susceptibility in the evaluation of reproductive toxins.

Journal Articles on this Report : 2 Displayed | Download in RIS Format

Publications Views
Other project views:	All 6 publications	6 publications in selected types	All 6 journal articles

Publications
Type	Citation	Project	Document Sources
Journal Article	Wang XB, Zuckerman B, Kaufman G, Wise P, Hill M, Niu TH, Ryan L, Wu D, Xu XP. Molecular epidemiology of preterm delivery: methodology and challenges. Paediatric and Perinatal Epidemiology 2001;15(Suppl 2):63-77	R825818 (2000) R825818 (Final)	not available
Journal Article	Wang X, Zuckerman B, Pearson C, Kaufman G, Chen C, Wang G, Niu T, Wise P, Bauchner H, Xu X. Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA-Journal of the American Medical Association 2002, Volume: 287, Number: 2 (JAN 9), Page: 195-202.	R825818 (2000) R825818 (Final)	not available

Supplemental Keywords:

candidate genes, gene polymorphisms, preterm delivery, transmission/disequilibrium test, TDT, case-control study, maternal cigarette smoking, genetic susceptibility, gene-environment interaction, birthweight, gestational age., Health, Scientific Discipline, Air, Geographic Area, Toxics, International, Risk Assessments, Chemistry, HAPS, Environmental Chemistry, 33/50, air toxics, Genetics, Benzene (including benzene from gasoline), toxic environmental contaminants, benzene, human exposure, genetic analysis, Toluene, genetic susceptibility, developmental effects, aromatic solvents, China, reproductive health, biomarker, blood samples, Styrene

Progress and Final Reports:

Original Abstract

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.