PHARMACOGENETIC DETERMINANTS OF FETAL SOMATIC MUTATION

吸烟和饮酒等母亲生活方式因素 众所周知，摄入是子宫内最普遍的来源 暴露于有毒物质并明显影响新生儿的健康 孩子们。我们的目标是解决关于 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 异种生物代谢的种族间差异被认为是 导致观察到的疾病易感性变化的主要因素。 这项提案将评估环境和环境的假设 生物活性和解毒酶活性的遗传决定因素 外源物质是调节经胎盘DNA的重要因素 损坏。这项提议与正在进行的排雷中心资助的 GRANT 5 R01 HD33016题为《生活方式因素对胎儿体细胞的影响 突变“，P.I.W.L.Bigbee。这项家长研究正在投资 在获取临床和流行病学方面的大量资源 1,500名妇女和新生儿的特征 并正在应用几种分子生物标记物 曝光率和效果。这些生物标志物包括4-羟色胺的测定 氨基联苯血红蛋白加合物水平和突变频率水平 在两个独立的基因座(血糖素A和次黄嘌呤磷酸核糖 转移酶)。 对于这些相同的受试者，我们建议将基因分型分析应用于这两个 孕妇和新生儿血液样本中的多态酶 参与香烟烟雾中化学物质的新陈代谢， 特别是CYP1A1、CYP2E1、GSTM1、GSTT1、NAT1*和NAT2*。筛选 逆转录聚合酶链式反应检测细胞色素P1A1、细胞色素P1B1和细胞色素P450 2E1mRNA的表达 外周血中的单个核细胞也将作为 酶表型活性和烟草烟雾暴露的生物标志物。 来自该基因型的药物遗传学信息与 包含社会人口统计信息的个体表型数据 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联系 代谢酶基因的表达及其存在的问题 特定的等位基因变异，以诱导遗传损伤 新生儿。迄今获得的产妇样本的初步数据 支持这一假设的血液样本继续被储存到 确保每个主题的完整信息可用。这 拟议的调查，在正在进行的资助研究范围内， 因此代表着一种非常强大且经济高效的策略 调查遗传风险因素的相对贡献和 母亲环境交互作用对新生儿DNA易感性的影响 损坏。

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.