Cigarette smoke-induced human fetal growth restriction

描述(由申请人提供)：研究表明，孕妇在怀孕期间接触香烟烟雾与不良妊娠发育密切相关，特别是胎儿生长受限(FGR)。除了产科并发症，FGR还涉及对成人健康、发病率甚至死亡率的长期影响。为了阐明吸烟引起FGR的机制，我们将使用吸烟和不吸烟孕妇的胎盘、母亲血和脐带血样本，这些样本的FGR程度已知。我们的假设是，环境中香烟烟雾毒素可以诱导人类生长因子基因的改变，特别是胰岛素样生长因子-1(IGF-1)，当表达的异常基因产物不能适当调节生长发育时，就会产生FGR。与吸烟相关的基因改变(多态)可能是毒素解毒所需的酶失效以及酶激活与DNA结合的反应产物(加合物形成)所致。这会导致DNA多态和异常基因产物的表达。我们研究的主要焦点将是IGF-1。将评估胎盘IGF-1基因的多态和核酸序列的变化。将对孕妇和脐带血中的IGF-1基因表达产物进行检测和表征。激活的毒素和胎盘IGF-1基因之间的加合物形成将被评估。由于解毒与激活的过程涉及特定的酶，将通过评估多环芳香烃(PAH)的解毒或激活为与DNA结合的反应产物来测量吸烟和不吸烟母亲的受影响和未受影响的怀孕(由血清尼古丁和可替宁检测控制)。类似的研究将在培养的早孕绒毛样本细胞(CVS)上进行。最后，通过对同一妊娠早期(CVS)和分娩后胎盘的IGF-1基因进行基因分型，我们将确定吸烟的早期和晚期影响，并确定吸烟导致FGR的高风险妊娠。如果成功，这种测试可能会有相当大的临床实用价值。

DESCRIPTION (provided by applicant): Studies have shown that maternal exposure to cigarette smoke during pregnancy correlates significantly with adverse conceptus development, especially fetal growth restriction (FGR). In addition to obstetrical complications, FGR has been implicated in long-term effects on adult health, morbidity and even mortality. To elucidate the mechanisms of cigarette smoke-induced FGR we will use samples of placentae, maternal blood and cord blood from smoking and non-smoking pregnancies whose degree of FGR are known. Our hypothesis is that alteration of human growth factor genes, specifically insulin-like growth factor-1 (IGF-1), can be induced by environmental exposure to cigarette smoke toxins and produce FGR when the expressed abnormal gene products fail to properly regulate growth and development. Smoking-related gene alterations (polymorphisms) can result from the failure of enzymes required for detoxification of toxins coupled with enzymatic activation to reactive products that bind with DNA (adduct formation). This leads to DNA polymorphism and expression of abnormal gene products. The primary focus of our studies will be IGF-1. Placental IGF-1 gene will be assessed for polymorphism and alteration of nucleic acid sequences. IGF-1 gene expression products in maternal and cord blood will be determined and characterized. Adduct formation between activated toxins and the placental IGF-1 gene will be assessed. Since the process of detoxification versus activation involves specific enzymes, these will be measured in affected and non-affected pregnancies from smoking and non-smoking mothers (controlled by serum nicotine and cotinine assays) by assessing detoxification or activation of polynuclear aromatic hydrocarbons (PAH) into reactive products that bind with DNA. Similar studies will be performed on cultured chorionic villus sample cells from first trimester (CVS). Finally, by genotyping of the IGF-1 gene in the first trimester (CVS) and post delivery placentas during the same pregnancy we will determine both early and late effects of smoking, and identify pregnancies with high risk of smoking-induced FGR. If successful, such testing could be of considerable clinical utility.