BIOMARKERS OF NEUROTOXICITY ASSOCIATED WITH FETAL TOBACCO SMOKE EXPOSURE?

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 大约有4500万美国成年人是活跃吸烟者。香烟烟雾由4000多种化合物组成，包括多环芳烃、一氧化碳、氰化氢和砷。尼古丁是香烟的主要成瘾成分，在戒断后第3天迅速代谢为可替宁，并全身清除。缺乏尼古丁清除后存在的香烟烟雾暴露的生物标志物，以及持续神经毒性的外周标志物。第一项研究（2009年4月至12月）的重点是确定组织蛋白质和代谢物稳态的异常，这些异常通过毒性的血清标志物反映。 在目前的提案（2010年1月至3月）中，我们正在确定酒精暴露诱导的IUGR是否由子宫/胎盘磷脂的可用性介导。 胎儿酒精谱系障碍（FASD）影响每100个活产婴儿中约1个，其中低出生体重和发育迟缓最常见。在FASD的啮齿动物模型中，妊娠期暴露于乙醇诱导胚胎吸收增加和宫内生长受限（IUGR）;持续的神经认知和行为缺陷;以及各种颅面畸形，包括小眼症和小头畸形。 在FASD模型中，在蜕膜化/胎盘形成过程中补充磷脂前体[胆碱或ω-3长链多不饱和脂肪酸（ω-3 LC-PUFA;鱼油补充剂）]可使IUGR恶化。 花生四烯酸利用率成功着床、蜕膜化和胎儿生长的既定介质--由磷脂转运/代谢介导。 在接下来的一年里，我们将探讨母亲饮酒是否会改变子宫/胎盘脂质环境，导致IUGR和LBW。 此外，我们将研究是否与LC-PUFAs或胆碱，据报道，以减轻LBW的母体营养补充，将修改子宫/胎盘脂质谱。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Approximately 45 million U.S adults are active smokers. Cigarette smoke consists of more than 4000 chemical compounds including polycylic aromatic hydrocarbons, carbon monoxide, hydrogen cyanide, and arsenic. Nicotine, the primary addictive component of cigarettes, is rapidly metabolized to cotinine with a systemic clearance by day 3 post-withdrawal. Biomarkers of cigarette smoke exposure which are present post-nicotine clearance, and which are peripheral markers of sustained neurotoxicity, are lacking. The emphasis of the first study (April-December 2009) was upon identification of abnormalities in tissue protein and metabolite homeostasis which are mirrored by serum markers of toxicity. In the current proposal (Jan-March 2010), we are establishing whether alcohol exposure induced IUGR is mediated by uterine/placental phosphatide availability. Fetal Alcohol Spectrum Disorders (FASD) affect approximately 1 per 100 live births of which low birth weight (LBW) and developmental delays are most common. In rodent models of FASD, gestational exposure to ethanol induces increased embryo resorption and intrauterine growth restriction (IUGR); persistent neurocognitive and behavioral deficits; as well as a variety of craniofacial malformations including microphthalmia and microcephaly . In FASD models, supplementation with phosphatide precursors [choline or omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFAs; fish oil supplement)] during decidualization/placentation alleviates IUGR. Arachidonic acid availabilityan established mediator of successful implantation, decidualization, and fetal growth--is mediated by phosphatide transport/metabolism. In the coming year, we will probe whether maternal alcohol consumption modifies the uterine/placental lipid environment leading to IUGR and LBW. Further we will examine whether maternal nutrient supplementation with LC-PUFAs or choline, which is reported to alleviate LBW, will modify the uterine/placental lipid profiles.