PERINATAL ESTROGEN, OXIDATIVE DAMAGES & UTERINE LESIONS

围产期雌激素、氧化损伤

基本信息

批准号：
6694054
负责人：
DEODUTTA ROY
金额：
$ 20.33万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-01-08 至 2004-09-01
项目状态：
已结题

项目摘要

DESCRIPTION: (Adapted from the Applicant's Abstract): The goal of this application is to characterize the molecular changes that underlie the development of estrogen-induced uterine lesions, including cancer. Neonatal exposure of hamsters to diethylstilbestrol (DES) or natural estrogen produces uterine tumors. Our preliminary studies revealed that exposure of neonatal hamsters to DES leads to induction of myeloperoxidase and hyperproduction of proinflammatory cytokines, TNF-alfa and IL-1B in the uteri of the pubertal animals. Compared to unexposed controls, the pubertal hamsters that had been exposed to DES neonatally exhibited a several-fold increase in 8-OH-dG levels and mutations in the uterine DNA. These findings led us to postulate that estrogen exposure of neonates results in imprinting that predisposes the pubertal animal to develop uterine cancer. The objectives of this application are: (1) to further elucidate the molecular consequences of estrogen exposure, with a focus on identifying whether hyperproduction of proinflammatory cytokine lL-1B and TNF-alfa in the uterus due to neonatal imprinting by estrogen exposure is involved in the etiopathology of uterine lesions; and (2) to examine whether hyperproduction of IL-1 J3 as a consequence of alterations in susceptibility genes in the uterus is involved in estrogen-induced uterine cancer. The specific aims are: 1. To determine how perinatal estrogen exposure leads to persistent hyperproduction of proinflammatory cytokines IL-1B and TNF-alfa in the pubertal period in the organ in which cancer develops, the uterus. 2. To determine whether the sensitivity of the uterus to neonatal estrogen that results in persistent hyperproduction of IL-1 f3 and TNF-alfa in the uteri of pubertal animals is controlled genetically. 3. To determine if persistent hyperproduction of IL-1B and TNF-alfa resulting from neonatal exposure produces instability in the uterine genome. 4.To determine whether persistent hyperproduction of IL-1B and TNF-alfa associated with neonatal exposure triggers oxidative damage to the genome through reactive oxidants leading to the development of uterine lesions, particularly cancer. These studies will provide key information concerning the mechanistic basis for the association of neonatal imprinting of the uterus in response to estrogen with subsequent persistent inflammatory responses and their role in damage to the genome through the formation of mutations in uterine susceptibility genes. They also will provide a new paradigm for analyzing how exposure of the uterus to synthetic and natural estrogens during the perinatal period might alter the uterine genome during development, which, in turn, may predispose an individual to the development of adverse effects, including cancer.

描述：（改编自申请人的摘要）：本次会议的目标应用是表征潜在的分子变化雌激素引起的子宫病变（包括癌症）的发展。新生儿仓鼠接触己烯雌酚 (DES) 或天然雌激素会产生子宫肿瘤。我们的初步研究表明，新生儿接触仓鼠吃 DES 会导致髓过氧化物酶的诱导和髓过氧化物酶的过度生成青春期子宫中的促炎细胞因子、TNF-α 和 IL-1B 动物。与未暴露的对照组相比，接受过暴露的青春期仓鼠暴露于 DES 的新生儿 8-OH-dG 水平增加数倍以及子宫DNA的突变。这些发现使我们假设新生儿的雌激素暴露会导致印记，从而导致青春期动物罹患子宫癌。此应用程序的目标是：（1）进一步阐明雌激素暴露的分子后果，重点是确定促炎细胞因子是否过度产生由于雌激素的新生儿印记而导致子宫内的 lL-1B 和 TNF-α 暴露与子宫病变的病因病理有关； (2) 至检查 IL-1 J3 的过度产生是否是由于子宫内的易感基因参与雌激素诱发的子宫癌症。具体目标是： 1. 确定围产期雌激素暴露情况导致促炎细胞因子 IL-1B 持续过量产生， TNF-α 在青春期发生癌症的器官中，子宫。 2.确定子宫对新生儿是否敏感雌激素导致 IL-1 f3 和 TNF-α 持续过量产生青春期动物的子宫是受基因控制的。 3. 判断是否新生儿导致的 IL-1B 和 TNF-α 持续过量产生暴露会导致子宫基因组不稳定。 4.判断是否与新生儿相关的 IL-1B 和 TNF-α 持续过量产生暴露通过活性氧化剂引发基因组氧化损伤导致子宫病变，特别是癌症的发展。这些研究将提供有关机制基础的关键信息新生儿子宫印记与雌激素反应的关系随后的持续炎症反应及其在损伤中的作用基因组通过子宫易感基因突变的形成。他们还将提供一个新的范例来分析子宫如何暴露于围产期合成和天然雌激素可能会改变发育过程中的子宫基因组，这反过来又可能使个体易感导致包括癌症在内的不良反应的发生。