REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF DIOXIN

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The goal is to determine consequences perinatal TCDD exposure on prostate development in the C57BL/6 mouse and elucidate the mechanisms involved. Specific aims are to identify aberrant effects of TCDD on development of ventral, dorsolateral, and anterior prostate and to determine using aryl hydrocarbon receptor (AhR) knockout (AhRKO) mice if these effects require AhR. The specific aims of the proposal are: 1) to determine critical periods for producing TCDD effects and elucidate androgen-dependent mechanisms involved in causing them. 2) to assess if TCDD acts directly on urogenital sinus (UGS) to disrupt prostate development and if AhR is required in UGS mesenchyme or epithelium to cause certain effects. 3) to evaluate if coexposure to a natural AhR antagonist in human food, resveratrol, ameliorates TCDD disruption of prostate development. 4) to identify TCDD-responsive genes in UGS and determine which ones are involved in TCDD inhibition of prostate budding. 5)to determine the long-term consequence of perinatal TCDD exposure on prostate size, histology, and growth regulation in senescent mice. Hypotheses to be tested are that perinatal TCDD exposure inhibits prostatic bud formation, ductal branching morphogenesis, ductal canalization, luminal cell differentiation and prostatic secretory function, and may alter normal age-related changes in androgen dependence. The long-range goal is to identify genes that are the most sensitive to TCDD exposure and whose altered expression may be critical for producing particular aberrant prostate effects later in life. Genes implicated in prostate development including those for proto-oncogenes, transcription factors, homeobox genes, growth factors, and cell adhesion molecules, will be assessed for differential expression along with other genes. The innovation in this approach is that, for the first time, it may shed light on TCDD-induced alterations in gene expression during fetal stage of development that cause latent, adverse effects on the prostate. The human health significance is that aberrant effects on prostate development are among the most sensitive and highly reproducible responses to TCDD in animals. AhR and ARNT are expressed in human fetal, benign hyperplastic, and malignant prostate, suggesting that human prostate responds to TCDD. There is an extraordinarily high incidence of benign prostate hyperplasia (BPH) and prostate cancer in humans, yet the function of AhR signaling in human prostate remains unknown. The proposed research may clarify the mechanisms by which TCDD disrupts early prostate development and possibly prostate growth in senescence and provide insight into naturally occurring chemicals in the human diet that may ameliorate the adverse development effects of TCDD on the prostate.