REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF DIOXIN

目标是确定围产期TCDD暴露对 C57BL/6小鼠前列腺发育及其机制的研究 牵涉其中。具体目标是确定TCDD对发育的异常影响 腹侧、背侧和前侧的前列腺，并用芳香烃测定 碳氢受体(AhR)基因敲除(AhRKO)小鼠，如果这些效应需要AhR。 该提案的具体目标是：1)确定 产生TCDD效应并阐明雄激素依赖机制 导致了它们的产生。2)评估TCDD是否直接作用于泌尿生殖窦(UGS) 干扰前列腺发育，如果UGS间充质细胞或 上皮细胞会引起一定的影响。3)评估共同暴露在天然环境中是否 人类食物中的AHR拮抗剂白藜芦醇改善TCDD的干扰 前列腺发育。4)鉴定UGS中TCDD反应基因并确定 哪些基因参与了TCDD抑制前列腺发芽的作用。5)确定 围产期接触TCDD对前列腺大小的长期影响， 衰老小鼠的组织学和生长调节。需要检验的假设是 围产期接触TCDD抑制了前列腺芽的形成、导管的分枝 形态发生、导管管化、腔细胞分化与前列腺 分泌功能，并可能改变正常的年龄相关的雄激素变化 依赖。长期目标是确定哪些基因是 对TCDD暴露敏感，其表达变化可能对 在以后的生活中产生特殊的异常前列腺效应。涉及的基因 在包括原癌基因在内的前列腺发育过程中，转录 同源异型盒基因、生长因子和细胞黏附分子等因子将成为 评估与其他基因的差异表达。中国的创新 这种方法可能第一次揭示由TCDD引起的 导致胎儿发育阶段基因表达变化的原因 对前列腺有潜在的不良影响。对人类健康的意义在于 对前列腺发育的异常影响是最敏感和 动物对TCDD的高度重复性反应。AHR和ARNT表示为 人类胎儿、良性增生症和恶性前列腺，提示人类 前列腺对TCDD有反应。良性疾病的发生率非常高。 前列腺增生症(BPH)和前列腺癌，但其功能 AHR在人前列腺中的信号转导机制尚不清楚。拟议的研究可能 阐明TCDD干扰早期前列腺发育和 可能是前列腺在衰老过程中的生长，并提供了对自然 人类饮食中可能改善不良反应的化学物质 TCDD对前列腺发育的影响

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.