Reproductive Health, Serum Dixon, and P450 Genes in Vietnam Veterans

EPA Grant Number: R825817
Title: Reproductive Health, Serum Dixon, and P450 Genes in Vietnam Veterans
Investigators: Sweeney, Anne , Cooper, Sharon , Denison, Michael , Symanski, Elaine , Wu, Xifeng , Wun, Chuan-Chuan
Current Investigators: Sweeney, Anne , Cooper, Sharon , Denison, Michael , Junco, Deborah del , Symanski, Elaine , Wu, Xifeng , Wun, Chuan-Chuan
Institution: The University of Texas at Houston
EPA Project Officer: Hahn, Intaek
Project Period: November 19, 1997 through November 18, 2000 (Extended to November 30, 2002)
Project Amount: $874,195
RFA: Issues in Human Health Risk Assessment (1997) RFA Text |  Recipients Lists
Research Category: Health Effects , Human Health Risk Assessment , Health


In the 1996 update by the Institute of Medicine's Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides, it was concluded that there was "limited/suggestive evidence" of an association between paternal herbicide exposure and spina bifida in the offspring of male Vietnam veterans. Much of the concern is with regard to the dioxin contamination present in herbicides used during the Vietnam War. Dioxin exposure, however, is not limited to Vietnam veterans and a "safe threshold" for dioxin exposure has never been established for the U.S. general population. The contradictory findings of previous research relating dioxin and adverse reproductive effects may be due in part to the absence of a genetic susceptibility component to identify high-risk subpopulations. The proposed case-control study is designed to test the hypothesis that the interaction between parental P450 genotype and dioxin exposure increases the risk of neural tube defects (NTDs), using Vietnam era veterans as the study population.


A listing of all NTDs diagnosed in the U.S. between 1965-1990 will be obtained from birth certificates, fetal death certificates and death certificates (for older offspring). This interval represents the majority of childbearing years for Vietnam era veterans. Vietnam era and theater service will be ascertained through linkage with Department of Defense and Department of Veterans Affairs databases. Cases (a veteran parent of an offspring with an NTD born between 01/01/65-01/01/90) and controls (a veteran parent of a liveborn infant free of NTDs) will be selected from pregnancies in which either parent was a Vietnam era veteran. An Exposure Index that has been developed based on military occupational specialty, the years served in Vietnam, and service in Vietnam for women veterans will classify all subjects. Individuals will be selected from the high, medium, and low exposure probability strata for the in-depth case-control evaluation phase. Current addresses for selected participants will be obtained through an existing interagency agreement with NIOSH, the IRS, the SSA, and the Department of Veterans Affairs. Participants will be asked to complete a mailed questionnaire detailing demographic and lifestyle characteristics, and medical, reproductive, occupational, and military histories. A blood sample will be collected at the VA Medical Center or outpatient clinic located nearest to the participant's home. All the samples will be subjected to a bioassay for detection of total dioxin-like activity. A subset of the samples, including all with readily detectable dioxin-like activity as well as a random sample of the remaining serum specimens, will undergo a quantitative dioxin analysis. In addition, all samples will be analyzed for CYP1A1 genotyping. One method will reveal Msp1 polymorphisms; the second detects an A/G substitution on exon 7 of the CYP1A1 gene, the genetic basis of an isoleucine/valine substitution. Data analysis will include crude and adjusted odds ratios for NTDs and high versus low dioxin levels as determined by the bioassay. Odds ratios for NTDs and each type of P450 allele will be calculated to test the hypothesis that among NTD-affected pregnancies, there will be a higher proportion of subjects with the variant allele compared with pregnancies in the control group. Finally, a multivariate analysis will be conducted to test for the interaction between P450 genotype and serum dioxin level and association with NTDs.

Expected Results:

This study will provide the first assessment of dioxin exposure among female Vietnam veterans and permit the evaluation of a maternally mediated effect. The study will also include Vietnam veterans who served in the earlier years of the conflict (1962-1966); an important group underrepresented in previous studies of Agent Orange exposure and health effects. Finally, this represents the first attempt to examine an underlying genetic susceptibility component to dioxin toxicity resulting in an adverse reproductive event.

Publications and Presentations:

Publications have been submitted on this project: View all 3 publications for this project

Supplemental Keywords:

neural tubedefects, dioxin, hersbicides, genetic polymorphisms, veterans, susceptibility, RFA, Health, Scientific Discipline, Toxics, Genetics, Epidemiology, Chemistry, pesticides, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, genetic susceptability, Biology, dioxin, sensitive populations, Vietnam veterans, spina bifida, P450 genes, exposure, human exposure, genetic polymorphisms, environmentally caused disease, human susceptibility, reproductive health, herbicides, dioxin exposure, genetic susceptibility

Progress and Final Reports:

  • 1998 Progress Report
  • 1999 Progress Report
  • 2000 Progress Report
  • 2001 Progress Report
  • 2002
  • Final Report