New Model Leading to Preterm Delivery: Role of Exposure to Environmental Toxins

说明(申请人提供)：早产是新生儿发病率和死亡率以及儿童神经系统残疾的主要原因，特别是在胎龄不到28周的婴儿中。尽管在照顾怀孕母亲方面取得了重大进展，但早产的发生率仍在上升。越来越多的人认识到，细胞因子和炎症介质，特别是前列腺素，存在于母胎界面，在调节分娩方面发挥着基础性作用。尤其重要的是抗炎细胞因子白介素10(IL-10)，它的功能是抑制启动分娩的胎盘微环境中的促炎抗胎儿免疫反应。我们推测，在存在亚临床感染的情况下，IL-10的减少会导致过度的炎症反应，从而促使母胎界面的局部免疫系统产生抗胎儿反应和早产。抑制胎盘中IL-10的潜在机制尚不清楚。TCDD(2，3，7，8-四氯二苯并-对二恶英)是一种持久性环境污染物，是废物焚烧的制造副产品，在农药混合物中被发现是一种污染物。流行病学研究表明，母亲接触TCDD与早产之间存在很强的相关性。众所周知，TCDD可以调节免疫反应，我们已经证明它可以阻断胎盘IL-10的产生。我们假设，宫内暴露于TCDD会导致IL-10的下调和/或促炎细胞因子的上调，从而在轻度感染的情况下引发早产。为了验证这一假设，计划进行以下研究：(1)比较早产、正常中期妊娠和足月分娩样本中人类胎盘产生的细胞因子；(2)分析IL-10在调节早产胎盘前列腺素分泌中的作用，并与正常中期妊娠和足月分娩样本进行比较；(3)表征TCDD对胎盘细胞因子表达和活性的影响；以及(4)确定TCDD是否增加感染诱导早产小鼠早产的易感性。公共卫生相关性：本申请中描述的研究将提高我们对早产的分子发病机制以及暴露于环境毒物在这一病理过程中的作用的理解。这些发现将对旨在确定更有效的早产预防和治疗策略的研究有用。

DESCRIPTION (provided by applicant): Preterm birth is a major cause of neonatal morbidity and mortality and childhood neurological disability particularly in infants born less than 28 weeks gestation. Despite significant advances in the care of pregnant mothers, the incidence of preterm labor is on the rise. There is growing recognition that cytokines and inflammatory mediators, in particular, prostaglandins, present at the maternal-fetal interface, play a fundamental role in regulating labor. Of particular importance is the anti-inflammatory cytokine, interleukin-10 (IL-10) which functions to inhibit the pro-inflammatory anti-fetal immune responses in the placental micro-environment that initiate labor. We speculate that in the presence of subclinical infection, decreases in IL-10 lead to an exaggerated inflammatory reaction that drives the local immune system at the maternal-fetal interface towards anti-fetal responses and preterm labor. Mechanisms underlying suppression of IL-10 in the placenta are unknown. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a persistent environmental pollutant, generated as a manufacturing byproduct of waste incineration, and is found as a contaminant in pesticide mixtures. Epidemiologic studies have suggested a strong association between maternal exposure to TCDD and preterm birth. TCDD is known to modulate immune responses and we have demonstrated that it blocks placental IL-10 production. We hypothesize that intrauterine exposure to TCDD leads to down regulation of IL-10 and/or up regulation of pro-inflammatory cytokines that can trigger preterm labor in the setting of low grade infection. To test this hypothesis, studies are planned to: (1) compare cytokines produced by human placentas from preterm, normal second trimester, and term labor samples; (2) Analyze the role of IL-10 in regulating placental prostaglandin production in preterm when compared to normal second trimester and term labor samples; (3) characterize the effects of TCDD on placental cytokines expression and activity, and (4) Determine if TCDD increases susceptibility to preterm delivery in infection-induced preterm labor in mice. PUBLIC HEALTH RELEVANCE: The studies described in this application will improve our understanding of the molecular pathogenesis of preterm labor and the role of exposure to environmental toxicants on this pathologic process. These findings will be useful in studies aimed at identifying more effective prevention and treatment strategies for preterm labor.