Cigarette smoke-induced human fetal growth restriction

描述（由申请人提供）：研究表明，孕妇在怀孕期间暴露于香烟烟雾与不良的胎儿发育，特别是胎儿生长受限（FGR）显著相关。除了产科并发症外，生育能力下降还涉及对成人健康、发病率甚至死亡率的长期影响。为了阐明香烟烟雾引起FGR的机制，我们将使用已知FGR程度的吸烟和非吸烟孕妇的胎盘、母体血液和脐带血样本。我们的假设是，当人类生长因子基因，特别是胰岛素样生长因子-1 （IGF-1）的表达异常的基因产物不能正常调节生长发育时，可以被环境暴露于香烟烟雾毒素诱导改变并产生FGR。与吸烟相关的基因改变（多态性）可能是由于毒素解毒所需的酶的失效，以及酶激活与DNA结合的反应产物（加合物形成）。这导致DNA多态性和异常基因产物的表达。我们的主要研究重点将是IGF-1。评估胎盘IGF-1基因的多态性和核酸序列的改变。IGF-1基因在母体和脐带血中的表达产物将被确定和表征。将评估活化毒素与胎盘IGF-1基因之间的加合物形成。由于解毒与激活的过程涉及特定的酶，这些将通过评估多核芳烃（PAH）的解毒或激活成与DNA结合的反应产物，在吸烟和不吸烟母亲的受影响和未受影响的怀孕中进行测量（由血清尼古丁和可替宁测定控制）。类似的研究将在培养的绒毛膜绒毛样本细胞从妊娠早期（CVS）进行。最后，通过对妊娠早期（CVS）和分娩后胎盘的IGF-1基因分型，我们将确定吸烟的早期和晚期影响，并确定吸烟诱发FGR的高风险妊娠。如果成功，这种测试将具有相当大的临床应用价值。

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.