Superfund Research Program
Organochlorine Disruption of the Wnt Gene Pathway in the Female Reproductive Tract
Project Leader: David Sassoon
Grant Number: P42ES007384
Funding Period: 2001 - 2006
- Project Summary
Project Summary (2001-2006)This project is examining a unique gene-environment interaction and its effect on development, namely the control by hormonally active organochlorines (OCs) of WNT genes in uterine growth and function. Loss of Wnt7a heterozygous females causes development of endometrial malformations resembling a precancerous condition (polycystic glandular hyperplasia) commonly found in post-menopausal women. Investigators are examining the action of OC compounds, typical of Hudson River contaminants in both normal (wild type) and mutant WNT animals. It is believed that OCs will exert similar effects to those that have been observed with the synthetic estrogen, DES. Specifically, project investigators hypothesize that OCs can de-regulate the normal pattern of Wnt gene expression, either during development or in the adult, leading to uterine, cervical or vaginal deformities. Further, the researchers propose that mice carrying deletions in one or several WNT genes will be more vulnerable to the effects of OC exposure. It has been shown that Wnt 5,5a, and 7a are regulated by steroid hormones and direct the correct development and cytoarchitecture of the reproductive tract. Project investigators are testing the effects of two OCs with opposing estrogenic properties: o,p'-DDT (estrogenic) and 3,3',4,4'-tetrachlorobiphenyl (anti-estrogenic). First, the scientists are characterizing and comparing Wnt gene expression in wild type female mice following treatment with these two environmental estrogens. Second, they will assess molecular and cellular effects of these two OC compounds Wnt mutant mice, heterozygous in one, two, or three Wnt 4,5, and 7a gene loci.
These findings will elucidate a new mechanism of action for OC residues common in Superfund hazardous waste sites. Both exposures and phenotypes will shed new light upon the role of OCs in human carcinogenesis and developmental toxicity. The data will have important implications for policy decisions pertaining to the management of OCs at Superfund sites.