MECH. OF PEROXISOME PROLIFERATOR ACTION ON TESTIS DEVEL.

描述：(改编自《调查者摘要》)：邻苯二甲酸酯类化合物 是无处不在的环境污染物，因为它们是内分泌的 具有微弱雌激素活性的干扰物，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酶体。 激活一种称为过氧酶体的受体的增殖物 增殖因子激活受体(PPAR)。这项提议的目标是 确定邻苯二甲酸酯的潜在分子和细胞机制 而过氧化物酶增殖物破坏了睾丸的功能。假设是 测试表明，暴露在邻苯二甲酸盐或其他过氧化物体增殖剂中会导致 PPAR激活，干扰维甲酸信号通路，即 对胚胎和出生后的睾丸发育至关重要。维甲酸的杂二聚体 酸性受体α(RARpha)和维甲酸X受体(RXR)是 睾丸功能正常。RXR还与PPAR形成异二聚体，这是 转录活性所必需的，因此RXR是 维甲酸和过氧化物酶增殖物的作用。具体目标是 确定邻苯二甲酸盐和其他过氧酶体的信号机制 增殖因子激活PPAR，表明PPAR可能干扰正常 睾丸中的维甲酸信号。剂量依赖与发育 -PPAR、维甲酸受体和靶点表达的特异性变化 与脂质、维甲酸或类固醇新陈代谢有关的基因将在 胚胎和出生后大鼠的睾丸。和PPARpha基因敲除小鼠的睾丸 用邻苯二甲酸盐和其他过氧化物酶增殖剂治疗。公安部还将 检测过氧化物酶体增殖物对转录激活的影响 支持细胞中PPAR和维甲酸受体的表达 RXR的潜在竞争对手。过度表达RARAlpha或PPARAlpha将是 实现以确定PPARpha和RARpha是否竞争内源性 RXR。结果将证明，接触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激酶活性增加所介导，以及 FSH和cAMP活性降低，这种激活会导致改变 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的作用机制 和其他过氧化物酶体增殖物改变睾丸功能并有助于 我们对这些化合物对人类健康风险的理解。 了解分子信号转导机制可能有助于 筛选与邻苯二甲酸酯性质相似的其他化学物质的方法 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.