This project will examine 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 leads to conditions in the uterus which closely resemble the situation in women exposed to DES in utero, and Wnt7a heterozygous females develop endometrial malformations resembling a pre-cancerous condition (polycystic glandular hyperplasia) commonly found in post-menopausal women. We propose to examine the action of OC compounds, typical of Hudson River contaminants in both normal (wildtype) and mutant WNT animals. We reason that OCs will exert similar effects to those we have observed with the synthetic estrogen, DES. Specifically, we propose 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. We further propose that mice carrying deletions in one or several WNT genes will be more vulnerable to the effects of OC exposure. We have shown that Wnt 4,5a, and 7a are regulated by steroid hormones and direct the correct development and cytoarchitecture of the reproductive tract. To test our hypotheses, we will test the effects of two OCs with opposing estrogenic properties: o,p?-DDT (estrogenic) and 3,3' 4,4'-tetrachlorobiphenyl (anti-estrogenic). First, we will characterize and compare Wnt gene expression in wildtype female mice following treatment with these two environmental estrogens. Second, we will assess molecular and cellular effects of these two OC compounds in 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.
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