This is a resubmitted R01 application that seeks to test the hypothesis that the reproductive effects of xenobiotics are not limited to the actions of the ER. This hypothesis will be tested by a comparison of the effects of two xenoestrogens, Kepone (chlordecone) and O,P'-DDT and a non-estrogenic analog of DDT (P,P'-DDD) with those of two natural estrogens, estradiol and 4-hydroxy-estradiol, on the expression of several uterine genes in normal animals and those in which the ER is either lacking (transgenic ER knock-out) or inactivated by a pure antiestrogen. The applicant proposes to determine the effect of these agents on: 1. expression of two early response genes, c-fos and c-jun; 2. expression of genes controlling heparin binding-epidermal growth factor like growth factor (HB-EGF) and amphiregulin (AR), two growth factors associated with embryo implantation; 3. expression of two well known estrogen responsive genes for lactoferrin (LF) and progesterone receptor (PR). Studies will also be done to determine the separate and interactive effects of progesterone (P), xenoestrogens and the natural estrogens on the expression of these uterine genes in ovariectomized mice with and without a functional ER (ERKO mice). Morphological and physiological consequences of expression will be tested using: 1. changes in uterine wet and dry weight for protein synthesis; 2. cell specific incorporation of tritiated thymidine to measure DNA synthesis; and 3. immunohistochemical localization of proliferating cell nuclear antigen to indicate cellular hyperplasia. The results are expected to provide the basis for new approaches to understand the mechanisms involved in reproductive toxicity.
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