PHARMACOGENETIC DETERMINANTS OF FETAL SOMATIC MUTATION

母亲的生活方式因素，如吸烟和饮酒 消费是已知的最普遍的来源，在子宫内 接触有毒物质，明显影响新生儿的健康 孩子 我们的目标是解决有关的根本问题 遗传背景在多大程度上调节了 环境暴露对DNA损伤程度的影响 个体间和 异生物质代谢的种族间差异被认为是 主要贡献者观察到的疾病易感性的变化。 该提案将评估环境和 生物活化和解毒酶活性的遗传决定因素 外源性物质是调节经胎盘DNA的重要因素 损害 这项建议与正在进行的国家排雷中心资助的 授予5 R 01 HD 33016，题为“影响胎儿躯体健康的生活方式因素 突变”，私家侦探。W. L.大蜜蜂 这项家长研究 在获得临床和流行病学方面的大量资源 对1,500名妇女和新生儿进行了广泛的定性分析， 社会人口谱，并正在应用几种分子生物标志物， 曝光和效果。 这些生物标志物包括测定4- 氨基联苯血红蛋白加合物水平和突变频率水平 在两个独立的位点（血型糖蛋白A和次黄嘌呤磷酸核糖基 转移酶）。 对于这些相同的受试者，我们建议将基因分型测定应用于 母亲和新生儿的血液样本，侧重于多态酶 参与香烟烟雾中化学物质的代谢， 特别是CYP 1A 1、CYP 2 E1、GSTM 1、GSTT 1、NAT 1 * 和NAT 2 *。 筛选 通过RT-PCR检测CYP 1A 1、CYP 1B 1和CYP 2 E1的mRNA表达水平 在外周血单核细胞中，也将作为 酶表型活性和暴露于烟草烟雾的生物标志物。 整合来自该基因型的药物遗传学信息， 表型数据和社会人口统计学信息， 测量的环境风险因素和测量的暴露/影响 生物标志物，将使研究之间的具体关联 代谢酶基因的表达和 特异性等位基因变异，以诱导遗传损伤， 新生儿 迄今获得的母体样本的初步数据 支持这一假设，血液样本继续储存， 确保每个受试者的完整信息可用性。 这 拟议的调查，在正在进行的资助研究的背景下， 因此，这是一个非常强大和具有成本效益的战略， 研究遗传风险因素的相对贡献， 母体环境相互作用对新生儿DNA易感性的影响 损害

Maternal lifestyle factors such as cigarette smoking and alcohol consumption are known to be the most prevalent sources of in utero exposure to toxic substances and clearly impact the health of newborn children. Our goal is to address the fundamental question concerning the extent to which genetic background modulates the impact of environmental exposures on levels of DNA damage. Interindividual and interethnic differences in xenobiotic metabolism are considered to be major contributors to variations observed in disease susceptibility. This proposal will evaluate the hypothesis that environmental and genetic determinants of enzyme activities which bioactivate and detoxify xenobiotics are important factors in modulating transplacental DNA damage. This proposal is directly linked to the ongoing NICHD funded grant 5 R01 HD33016 entitled "Lifestyle Factors Affecting Fetal Somatic Mutation", P.I. W. L. Bigbee. This parent study is investing substantial resources in the acquisition of clinical and epidemiological characterization of 1,500 women and newborns across a wide sociodemographic spectrum and is applying several molecular biomarkers of exposure and effect. These biomarkers include determination of 4- aminobiphenyl hemoglobin adducts levels and mutation frequency levels at two independent loci (glycophorin A and hypoxanthine phosphoribosyl transferase). For these same subjects, we propose to apply genotyping assays to both maternal and newborn blood samples focusing on the polymorphic enzymes involved in the metabolism of chemicals found in cigarette smoke, specifically CYP1A1, CYP2E1, GSTM1, GSTT1, NAT1*, and NAT2*. Screening by RT-PCR for the level of mRNA expression of CYP1A1, CYP1B1 and CYP2E1 in peripheral blood mononuclear cells will also be performed as biomarkers of enzyme phenotypic activity and exposure to tobacco smoke. The integration of pharmacogenetic information from this genotype and phenotype data with sociodemographic information for individually measured environmental risk factors and the measured exposure/effect biomarkers, will enable the study of the specific associations between the expression of the metabolizing enzyme genes and the presence of specific allelic variants, to the induction of genetic damage in newborns. Preliminary data from maternal samples acquired to date support this hypothesis and blood samples continue to be banked to ensure the availability of complete information for each subject. This proposed investigation, in the context of the ongoing funded study, therefore represents a very powerful and cost-effective strategy to investigate the relative contributions of genetic risk factors and maternal environmental interactions to newborn susceptibility to DNA damage.