The long-range goal is to understand how aryl hydrocarbon receptor (AHR) signaling pathway activation affects prostate development and prostate disease. The developing prostate is highly sensitive to 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), the prototypical AHR agonist. In mice, TCDD inhibits prostatic bud formation by the fetal urogenital sinus (UGS), prevents the ventral prostate lobe from forming, and permanently alters the structure and function of the other prostate lobes. Preliminary results show that ?-catenin is essential for normal prostate development and implicate aberrant ?-catenin signaling as the key mechanism by which TCDD causes prostate abnormalities. Hypotheses to be tested in wild-type and transgenic C57BL/6J mice are as follows:
Aim 1 : TCDD inhibits prostatic bud formation by decreasing ?-catenin signaling in basal urogenital sinus epithelium (UGE).
Aim 2 : TCDD down-regulates ?-catenin signaling by decreasing expression of canonical Wnts and Rspos, and/or by increasing expression of non-canonical Wnts, in urogenital sinus mesenchyme (UGM).
Aim 3 a-c: TCDD epigenetically alters gene expression in the fetal UGE, and does so via ?-catenin down-regulation;
Aim 3 d: In utero and lactational TCDD exposure causes the senescent prostate to retain the epigenetic signature seen in TCDD-exposed fetal UGE and to inappropriately retain androgen responsiveness characteristic of young control adults.
Aim 4 : In utero and lactational TCDD exposure accelerates prostate adenocarcinoma progression in Nkx3.1;Pten mice and TCDD treatment in adulthood does likewise. Results from Aims 1 and 2 will significantly advance our understanding of the mechanisms by which AHR agonists affect early prostate development, and may help explain how TCDD and related chemicals cause abnormal development of other organs that also develop via mesenchyme-induced epithelial budding and branching (e.g., breast and lung). As for long-term effects, it has already been established that in utero and lactational TCDD exposure causes the dorsolateral prostate to retain abnormally high androgen dependence into senescence, and increase susceptibility to a type of prostate tumor (neuroendocrine) that is uncommon in men.
Aims 3 and 4 will in part determine if low-level maternal TCDD treatment also increases (a) androgen responsiveness in the senescent dorsolateral prostate, and (b) susceptibility to prostate adenocarcinomas, the most common prostate tumor type in men.
Aim 4 will also determine if Nkx3.1;Pten mice are an appropriate model for studying the increase in prostate cancer seen in Vietnam veterans exposed to the TCDD-contaminated herbicide Agent Orange. The proposed research has a high likelihood of establishing that ?-catenin signaling abnormalities are key contributors to TCDD toxicity in mammals, and of establishing that fetal TCDD exposure creates an epigenetic signature in the prostate, one associated in adulthood with altered responses to androgens and with cancer.
The developing prostate in lab animals is exceptionally sensitive to the ubiquitous environmental contaminant TCDD;therefore, it is likely that the prostate in humans is also at risk. The proposed research will substantially increase our understanding of how exposure to TCDD and related chemicals early in life permanently changes the prostate and its susceptibility to disease. In addition, it includes the first controlled animal study of whether TCDD exposure in adulthood increases the risk of prostate adenocarcinoma, the most common type of prostate cancer in men. NARRATIVE The developing prostate in lab animals is exceptionally sensitive to the ubiquitous environmental contaminant TCDD;therefore, it is likely that the prostate in humans is also at risk. The proposed research will substantially increase our understanding of how exposure to TCDD and related chemicals early in life permanently changes the prostate and its susceptibility to disease. In addition, it includes the first controlled animal study of whether TCDD exposure in adulthood increases the risk of prostate adenocarcinoma, the most common type of pros- tate cancer in men.
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