The effects of several environmental chemical contaminants upon the reproductive system have been of public concern. Accumulation and persistence of these toxicants in the biosphere have accentuated their public health significance in spite of limited commercial production or use. Attempts at understanding the mechanisms by which these agents alter the reproductive system have centered upon their capacity to mimic some of the effects of the natural estrogens. Several studies have demonstrated that many of the toxins, or their metabolites, can interact with the classical intracellular estrogen receptor. However, not only are many of the consequences of binding with the receptor unknown, but we are becoming increasingly aware that not all of the effects of estrogens, or their mimics, can be accounted for by the classical estrogen receptor. Particularly relevant to the latter are the critical progesterone-estrogen interactions that are necessary to bring about the synchronized development of the embryo and uterus at the time of the establishment of pregnancy. Considerable evidence has accumulated indicating that growth factors are important autocrine and/or paracrine mediators of reproductive steroid hormone actions at the time of implantation. Furthermore, increased expression of proto-oncogenes may be part of the cascade between the initial interaction of estrogen with the cell and the ultimate response obtained. Our working hypothesis is that many xenobiotics are reproductive toxins by virtue of their ability to alter synthesis of growth factors growth factor receptors, and proto-oncogenes. Therefore we will determine, using in situ hybridization and immunocytochemical techniques, the cell- specific expression of epidermal growth factor (EGF), transforming growth factor-alpha(TGFalpha) and insulin-like growth factor-I (IGF-I) messenger RNAs and proteins in the uteri of rats exposed to each of three toxins O- P'-DDT, Methoxychlor, and Chlordecone. In addition, each of the compounds will be tested for its ability to increase expression of EGF and IGF-I receptors in the uterine epithelium, stroma and myometrium of immature, pregnant and pseudopregnant rats. Furthermore, the temporal synthesis, as evidenced by increased uptake of tritiated thymidine. The results will enhance our understanding of the mechanisms by which xenobiotics act on the uterus at the time of pregnancy establishment as well as their possible effects upon other tissues.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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University of Kansas
Schools of Medicine
Kansas City
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Johnson, D C (1996) Estradiol-chlordecone (Kepone) interactions: additive effect of combinations for uterotropic and embryo implantation functions. Toxicol Lett 89:57-64
Yamamoto, T; Chapman, B M; Johnson, D C et al. (1996) Cytochrome P450 17 alpha-hydroxylase gene expression in differentiating rat trophoblast cells. J Endocrinol 150:161-8
Johnson, D C; Crane, L H (1995) Inhibitory and stimulatory effect of oestrogens upon ovarian 17 alpha-hydroxylase/C17,20-lyase in immature hypophysectomized rats treated with gonadotrophin. J Endocrinol 145:59-67
Johnson, D C; Chatterjee, S (1995) The role of arachidonic acid and/or its metabolites in embryo implantation initiated by epidermal growth factor (EGF). Prostaglandins Leukot Essent Fatty Acids 52:29-33
Johnson, D C; Banerjee, S; Chatterjee, S (1995) Estradiol and chlordecone (Kepone) decrease adenosine 3'5'-cyclic monophosphate concentrations in the ovariectomized immature rat uterus. Proc Soc Exp Biol Med 210:33-8
Johnson, D C; Chatterjee, S (1993) Embryo implantation in the rat uterus induced by epidermal growth factor. J Reprod Fertil 99:557-9
Chatterjee, S; Johnson, D C (1993) Contrasting action of antiestrogen (ICI-182780) for preventing initiation of embryo implantation by estradiol or epidermal growth factor (EGF). Life Sci 53:1625-30
Johnson, D C; Chatterjee, S (1993) Epidermal growth factor (EGF) replaces estradiol for the initiation of embryo implantation in the hypophysectomized rat. Placenta 14:429-38
Johnson, D C; Sen, M; Dey, S K (1992) Differential effects of dichlorodiphenyltrichloroethane analogs, chlordecone, and 2,3,7,8-tetrachlorodibenzo-p-dioxin on establishment of pregnancy in the hypophysectomized rat. Proc Soc Exp Biol Med 199:42-8
Johnson, D C (1992) Cellular localization and factors controlling rat placental cytochrome P45017 alpha (CYP17): 17 alpha-hydroxylase/C17,20-lyase activity. Biol Reprod 46:30-8

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