MECH. OF PEROXISOME PROLIFERATOR ACTION ON TESTIS DEVEL.

描述：（改编自研究者摘要）：邻苯二甲酸酯化合物 是无处不在的环境污染物， 具有弱雌激素特性的干扰物，人们担心它们的毒性 对男性生殖器官的影响邻苯二甲酸酯也是过氧化物酶体 它激活一种叫做过氧化物酶体的受体 增殖物激活受体（proliferator-activated receptor，PPAR）。本提案的目的是 确定潜在的分子和细胞机制， 过氧化物酶体增殖物破坏睾丸功能。假设是 暴露于邻苯二甲酸盐或其他过氧化物酶体增殖剂会导致 过氧化物酶体增殖物激活体，它干扰类维生素A信号通路， 对胚胎和出生后睾丸发育至关重要。视黄酸的异二聚体 酸受体α（RAR α）和类维生素A X受体（RXR）是必需的， 正常的睾丸功能RXR还与PPAR形成异二聚体， RXR是其转录活性所必需的，因此RXR是一个共同的因子， 视黄酸和过氧化物酶体增殖剂作用。具体的目标是 确定邻苯二甲酸酯和其他过氧化物酶体 增殖物激活PPAR，并表明PPAR可能干扰正常的 睾丸中的类维生素A信号。剂量依赖性和发育 - PPAR、类维生素A受体和靶点的表达的特异性变化， 涉及脂质、类维生素A或类固醇代谢的基因将在 胚胎和出生后大鼠的睾丸。和来自PPARalpha敲除小鼠的睾丸 用邻苯二甲酸盐和其他过氧化物酶体增殖剂处理。PI还将 研究过氧化物酶体增殖物对转录激活的影响 的过氧化物酶体增殖物激活受体和维甲酸受体的支持细胞，以确定是否有一个 RXR的潜在竞争对手。RAR α或PPARalpha的过度表达将导致 以确定PPARalpha和RARalpha是否竞争内源性 RXR。结果将证明，暴露于邻苯二甲酸盐和其他 过氧化物酶体增殖物导致PPAR和RAR活化的改变 由蛋白激酶C和MAP激酶活性增加介导，和 FSH和CAMP的活性降低，这种激活将导致改变 目的基因在胚胎和出生后大鼠睾丸中的表达。 这项研究的完成将阐明邻苯二甲酸酯 和其他过氧化物酶体增殖物改变睾丸功能， 我们对这些化合物对人类健康风险的理解。 了解分子信号机制可能有助于发展一种 一种筛选具有与邻苯二甲酸酯相似性质的其他化学品的方法 对男性生殖系统的影响

DESCRIPTION: (Adapted from the Investigator's Abstract) : Phthalate compounds are ubiquitous environmental contaminants and because they are endocrine disruptors with weak estrogenic properties, there is concern about their toxic effects on male reproductive organs. Phthalates are also peroxisome proliferators which activate a receptor called the peroxisome proliferator-activated receptor (PPAR). The goal of this proposal is to identify the underlying molecular and cellular mechanisms by which phthalates and peroxisome proliferators disrupt testicular function. The hypothesis to be tested is that exposure to phthalates or other peroxisome proliferators cause PPAR activation which interferes with the retinoid signaling pathway that is vital for embryonic and postnatal testis development. A heterodimer of retinoic acid receptor alpha (RARalpha) and retinoid X receptor (RXR) is essential for normal testicular function. RXR also forms a heterodimer with PPAR which is required for its transcriptional activity, thus RXR is a common factor for retinoic acid and peroxisome proliferator action. Specific aims are to determine the signaling mechanisms by which phthalates and other peroxisome proliferators activate PPAR and show that PPAR may interfere with normal retinoid signaling in the testis. The dose dependent and developmental -specific changes in the expression of PPAR, retinoid receptors, and target genes involved in lipid, retinoid, or steroid metabolism, will be examined in testes from embryos and postnatal rats. and testes from PPARalpha knockout mice treated with phthalates and other peroxisome proliferators. The PI will also examine the effects of peroxisome proliferators on transcriptional activation of PPAR and retinoid receptors in Sertoli cells to establish whether there is a potential competition for RXR. Over expression of RARalpha or PPARalpha will be achieved to ascertain whether PPARalpha and RARalpha compete for endogenous RXR. The results will demonstrate that exposure to phthalates and other peroxisome proliferators leads to alteration in the activation of PPAR and RAR mediated by increased activities of protein kinase C and MAP kinase, and decreased activities of FSH and CAMP, and this activation will lead to altered expression of target genes in testes of embryonic and postnatal rats. Completion of this research will elucidate the mechanism by which phthalates and other peroxisome proliferators alter testicular function and contribute to our understanding of the health risks from these compounds to humans. Understanding the molecular signaling mechanism may facilitate development of a method to screen for other chemicals that have similar properties as phthalates on the male reproductive system.