Genetic Stress and Toxicant-Induced Pregnancy Disruption

遗传压力和有毒物质引起的妊娠中断

• 批准号: 6901538
• 负责人: SURENDRA SHARMA
• 金额: $ 23.36万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901538
• 关键词: dosage; environmental contamination; environmental exposure; gene environment interaction; genetic susceptibility; halobiphenyl /halotriphenyl compound; immunotoxicity; inflammation; interleukin 10; laboratory mouse; lipopolysaccharides; microarray technology; pregnancy immunology; pregnancy loss; premature infant animal; prenatal growth disorder; toxicant interaction; trophoblast

Many chemical compounds introduced into the environment by human activity are suspected of influencing reproductive outcome. Epidemiological evidence suggests that those living in the vicinity of Superfund sites experience adverse pregnancy outcomes such as premature fetal loss and birth, intrauterine growth restriction (IUGR), and low birth weight. However, little is known about the mechanistic basis of reproductive anomalies. The long-term objective of this work is to understand the impact of co-exposure to genetic and chemical stress on pregnancy outcome and to delineate basic mechanisms of immune programming of toxicant-induced pregnancy disruption. This research project proposes to establish a mouse model to understand how ubiquitous environmental contaminants such as polychlorinated biphenyls (PCBs), given at sub-toxic doses, influence gestation in animals deficient in pregnancy compatible cytokines such as interleukin-10 (IL-10) or in anti-inflammatory immunity as observed in STAT6-/- mice. We have recently demonstrated that sub-clinical inflammation when combined during pregnancy with IL-10 deficiency results either in fetal loss or premature birth depending on the gestational age-dependent induction of inflammation. Furthermore, these adverse pregnancy outcomes are uniquely associated with cytotoxic activation of uterine Natural Killer (uNK) cells and/or loss of regulatory T cell subpopulations. We hypothesize that chemical stress induced by sub-toxic doses of PCBs represents a physiologic counterpart of inflammation that predisposes to adverse pregnancy outcomes when combined with genetic disruptions in pregnancy compatible loci. The specific aims will address: 1) dose response and time dependence of exposure to PCBs or lipopolysaccharide (IPS) to influence pregnancy outcome in wild type and IL-10-/- or STAT6-/- mice, 2) uterine immune cell recruitment, NK cell cytotoxic activation, and trophoblast trafficking in response to PCS or LPS treatment, 3) restoration of pregnancy by IL-10 administration or depletion of NK cells in IL-10-/- mice exposed to PCBs, and 4) microarray analysis of differentially regulated genes in uteroplacental tissue from normal and toxicant-induced adverse pregnancy. Understanding the mechanisms underlying toxicant-induced pregnancy disruption in mice will be important for identifying bio-markers of pregnancy-associated disorders in humans.

人们怀疑许多通过人类活动引入环境的化合物会影响生殖结果。流行病学证据表明，居住在超级基金附近的人会经历不良怀孕结果，例如早产和出生，宫内内生长限制（IUGR）和低出生体重。但是，关于生殖异常的机理基础知之甚少。这项工作的长期目的是了解遗传和化学应激对妊娠结局的影响，并描述有毒诱发的妊娠中断的免疫程序的基本机制。 This research project proposes to establish a mouse model to understand how ubiquitous environmental contaminants such as polychlorinated biphenyls (PCBs), given at sub-toxic doses, influence gestation in animals deficient in pregnancy compatible cytokines such as interleukin-10 (IL-10) or in anti-inflammatory immunity as observed in STAT6-/- mice.我们最近证明，在怀孕期间与IL-10缺乏症合并后，胎儿丧失或过早出生，取决于妊娠年龄依赖炎症的诱导。此外，这些不良怀孕 结局与子宫天然杀伤（UNK）细胞的细胞毒性激活和/或调节性T细胞亚群的丧失是独特的。我们假设通过亚2剂量的PCB诱导的化学应激代表了炎症的生理性对应物，当与妊娠兼容基因座的遗传破坏结合时，易患妊娠结局。具体目的将解决：1）接触PCB或脂多糖或脂多糖（IP）的剂量反应和时间依赖性影响野生型和IL-10 - / - 或Stat6 - / - 小鼠的妊娠结局，2）子宫免疫细胞募集，NK细胞毒素的毒性治疗，以及在PCS或TROPHAST上的疗程，以及在PCS或TROPHAST上进行疗程3）暴露于PCB的IL-10 - / - 小鼠中NK细胞的耗竭，以及4）从正常和有毒物质引起的不良怀孕的子宫内组织中差异调节基因的微阵列分析。了解基本机制 小鼠毒物引起的妊娠破坏对于鉴定人类妊娠相关疾病的生物标志物很重要。