Cigarette smoke-induced human fetal growth restriction

描述（由申请人提供）：研究表明，母亲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，胎儿生长迟缓还对成人健康、发病率甚至死亡率产生长期影响。为了阐明香烟烟雾诱导的FGR的机制，我们将使用来自吸烟和不吸烟妊娠的胎盘、母血和脐带血样本，其FGR程度是已知的。我们的假设是，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），可以诱导环境暴露于香烟烟雾毒素，并产生FGR时，表达的异常基因产物不能正确调节生长和发育。与吸烟有关的基因改变（多态性）可能是由于解毒毒素所需的酶的失效，加上酶激活与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。我们研究的主要重点将是IGF-1。将评估胎盘IGF-1基因的多态性和核酸序列的改变。将测定和表征母体和脐带血中的IGF-1基因表达产物。将评估活化毒素和胎盘IGF-1基因之间的加合物形成。由于解毒与活化的过程涉及特定的酶，因此将通过评估多核芳烃（PAH）解毒或活化为与DNA结合的反应产物，在吸烟和非吸烟母亲的受影响和未受影响妊娠（通过血清尼古丁和可替宁测定控制）中测量这些酶。将对孕早期（CVS）培养的绒毛样品细胞进行类似的研究。最后，通过对同一次妊娠的前三个月（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，并确定吸烟诱导FGR的高风险妊娠。如果成功，这种测试可能具有相当大的临床实用性。

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.