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Extramural Research

Latent Effects of Gestational Exposure to Heptachlor

EPA Grant Number: R829439
Title: Latent Effects of Gestational Exposure to Heptachlor
Investigators: Baker, Dean
Current Investigators: Baker, Dean , Gollapudi, Sastry , Kesner, James , Luderer, Ulrike , Yang, Haiou
Institution: University of California - Irvine
Current Institution: University of California - Irvine , National Institute for Occupational Safety and Health
EPA Project Officer: Glenn, Barbara
Project Period: March 1, 2002 through February 28, 2005 (Extended to August 31, 2006)
Project Amount: $1,931,310
RFA: Endocrine Disruptors: Epidemiologic Approaches (2001)
Research Category: Endocrine Disruptors

Description:

The research will investigate whether gestational or lactational exposure to the chlorinated cyclodiene insecticide, heptachlor, permanently alters reproductive and immune function. The study is based on a well characterized episode in which the entire commercial milk supply on the Hawaiian island of Oahu was contaminated with heptachlor epoxide during a 15 month period (1981-82) resulting in gestational exposure to offspring of women who drank cows' milk during that period.

The study will evaluate two primary hypotheses: 1) that reproductive function in young adults who were exposed to heptachlor during gestation and/or breast feeding will be deficient compared to a control group, and 2) that immune system function will be altered in the heptachlor exposed compared to the control group. Secondary hypotheses are: 1) the biological indicators of reproductive and immune function will correlate with quantitative estimates of heptachlor exposure, and 2) there will be gender-specific changes in reproductive endocrine and immune function associated with the heptachlor exposure.

Approach:

The study will assess biological indicators of reproductive and immune function in 400 young adults who were in utero on Oahu at the time of the milk contamination and have resided their whole lives on Oahu. In addition, 200 unexposed comparison participants matched for age and ethnicity will be studied, including 100 long-term residents of Oahu who were not born on the island and 100 native residents of Neighbor Islands in Hawaii which were not impacted by the milk contamination. The study will primarily involve a representative population of young adults, born between 7/81 and 6/82, who participated in a recently completed study of neurobehavioral effects of this exposure, plus additional young adults recruited from the Neighbor Islands.

The study will assess sensitive biological indicators of reproductive and immune function. Hypothalamic-pituitary-gonadal axis function will be assessed by measuring serum reproductive hormone concentration: testosterone in men; estradiol and progesterone in women; and luteinizing hormone and follicle-stimulating hormone in both men and women. In the men, semen samples will be obtained for determination of sperm quality. The women will be asked to collect daily first morning urine specimens and to record detailed menstrual nistories for one menstrual cycle. Levels of luteinizing hormone, estrone-3-glucuronide (EG), and pregnanediol 3-alpha-glucuronide (PG) will be measured in the urine. Cell mediated (Th1) immunity will be evaluated by anitbody titer response to immunization with tetanus, a T cell dependent antigen, and multivalent pneumoccal vaccine, a T cell independent carbohydrate antigen. The proportion of Th1 and Th2 type CD4+ cell subsets in the peripheral blood will be assessed using in vitro analysis of cytokine expression following activation. Susceptibility of peripheral blood T cells to activation-induced cell death will be assessed using in vitro analysis of Fas (CD95) and its ligand (CD95L)expression, and the percentage of apoptotic T cells assessed with Annexin V staining, at basal level and following activation.

The analysis will compare reproductive and immune function measures between the Oahu-born group and the two comparison groups - non-Oahu born Oahu residents and the Neighbor Island group - controlling for relevant confounders. Secondary comparisons among the Oahu-born population will be made based on individual estimates of gestational and lactational heptachlor epoxide exposure during the milk contamination episode.

Expected Results:

It is anticipated that modest alterations in immunological, and possibly reproductive, function will be associated with the surrogate indicators of gestational exposure to heptachlor epoxide. Such findings for immunological function would be consistent with the results of animal experimental research. This findings would have the following implications: (1) it would demonstrate the relevance of multi-generation animal experimental models by documenting consistency with human effects in this unique "natural experiment"; (2) it would indicate the need for further experimental research to identify the mechanism of the developmental toxicity; and (3) it would support the past policy determinations in the United States to restrict or disallow use of chlorinated cyclodiene pesticides and encourage other nations in which these pesticides are still used to establish similar policies.

Supplemental Keywords:

Endocrine disruption, endocrine disruptors, epidemiology., RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Toxics, Geographic Area, Genetics, Environmental Chemistry, Health Risk Assessment, Chemistry, pesticides, Endocrine Disruptors - Environmental Exposure & Risk, endocrine disruptors, Risk Assessments, Physical Processes, Children's Health, Endocrine Disruptors - Human Health, International, health effects, pesticide exposure, puberty, risk assessment, childhood development, vulnerability, age-related differences, endocrine disrupting chemicals, exposure, exposure studies, gene-environment interaction, environmental mutagens, fertility, human malformation, particle exposure models, gestational exposure, developmental biology, Oahu, Hawaii, human exposure, insecticides, susceptibility, toxicity, cumulative environmental exposure, lactational exposure, estrogen metabloism, endocrine disrupting chemcials, latent effects, diet, environmental stressors, environmental toxicant, harmful environmental agents, reproductive processes, toxic environmental contaminants, embryonic development, biological markers, endometriosis, growth & development, Heptachlor, developmental disorders, epidemiologic studies, exposure assessment

Progress and Final Reports:
2002 Progress Report
2003 Progress Report
2004 Progress Report
2005 Progress Report
2006 Progress Report

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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.

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