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

导致早产的新模式：环境毒素暴露的作用

• 批准号: 7641974
• 负责人: Nazeeh N Hanna
• 金额: $ 23.76万
• 依托单位: NYU WINTHROP HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641974
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Aryl Hydrocarbon Receptor; Caring; Cells; Cervix Uteri; Childhood; Cytokine Network Pathway; Data; Deposition; Dinoprostone; Dioxins; Disease; Down-Regulation; Environment; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Exhibits; Exposure to; Fetal Membranes; Fetus; Genital system; Health; Human; Immune; Immune response; Immune system; Immunohistochemistry; Immunologics; Incidence; Incineration; Infant; Infection; Infection of amniotic sac and membranes; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-10; Lead; MAPK14 gene; Maternal Exposure; Maternal-Fetal Exchange; Mediating; Mediator of activation protein; Modeling; Molecular; Morphogenesis; Mothers; Mus; Neurologic; Organ; PTGS2 gene; Partner in relationship; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Pesticides; Phosphotransferases; Placenta; Play; Predisposition; Pregnancy; Pregnancy Complications; Premature Birth; Premature Infant; Premature Labor; Prevention; Production; Prostaglandin Production; Prostaglandins; Proteins; Reaction; Role; Sampling; Second Pregnancy Trimester; Signal Transduction; Testing; Tetrachlorodibenzodioxin; Time; Toxic Environmental Substances; Up-Regulation; base; cell type; cytokine; cytotoxic; cytotrophoblast; disability; fetal; human MAPK14 protein; improved; in utero; inhibitor/antagonist; mRNA Expression; macrophage; mortality; mouse model; myometrium; neonatal morbidity; pathogen; pregnant; prevent; public health relevance; research study; response; stem; treatment strategy; wasting

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.

描述（由申请人提供）：早产是新生儿发病率，死亡率和儿童神经疾病的主要原因，尤其是在妊娠不到28周的婴儿中。尽管怀孕母亲的照顾取得了重大进展，但早产的发生率仍在上升。越来越认识到，在母亲界面上存在的细胞因子和炎症介质，尤其是前列腺素，在调节劳动方面起着基本作用。尤其重要的是抗炎细胞因子白介素-10（IL-10），其功能可抑制启动劳动的胎盘微环境中促炎性的抗抗原免疫反应。我们推测，在存在亚临床感染的情况下，IL-10的降低会导致夸张的炎症反应，从而驱动母体 - 狂热界面处的局部免疫系统朝着抗狂热反应和早产。胎盘中IL-10抑制的机制尚不清楚。 TCDD（2,3,7,8-四氯迪本佐-P-二恶英）是一种持续的环境污染物，作为废物焚化的制造副产品产生，在农药混合物中被发现是污染物。流行病学研究表明，孕产妇接触TCDD与早产之间存在密切的联系。已知TCDD可以调节免疫反应，我们已经证明它阻止了胎盘IL-10产生。我们假设宫内暴露于TCDD会导致减少IL-10的调节和/或UP调节促炎性细胞因子，这些因子可以在低年级感染的情况下引发早产。为了检验这一假设，计划进行研究：（1）比较人胎盘从早产，正常孕期和术语劳动样本中产生的细胞因子； （2）与正常的孕期和期限劳动样本相比，分析IL-10在调节早产的胎盘前列腺素产生中的作用； （3）表征TCDD对胎盘细胞因子表达和活性的影响，并且（4）确定TCDD是否增加了小鼠感染诱导的早产的早产的敏感性。公共卫生相关性：本应用中描述的研究将提高我们对早产的分子发病机理以及对环境有毒物质在这种病理过程中的作用的理解。这些发现将在旨在确定早产劳动的更有效的预防和治疗策略的研究中很有用。