Genetics of Phthalate /Bisphenol Risk in Minority Groups

描述（申请人提供）：本分子遗传学项目的总体目标是评估基因？可能影响个体对ED易感性的环境相互作用， 发育神经毒物，这是该中心的整体科学主题。该计划是通过鉴定和表征PON 1，脂肪酶和UGT-葡萄糖醛酸转移酶的多态性和表达水平的变化来实现这一目标，所有这些都参与了ED和农药的代谢和解毒。本申请的具体目的是，邻苯二甲酸酯：1）检查唾液脂肪酶活性作为邻苯二甲酸二酯转化为邻苯二甲酸单酯的生物标志物; 2）确定人唾液腺中三种连锁的人脂肪酶基因的表达水平; 3）确定唾液人脂肪酶基因中常见多态性的频率和唾液脂肪酶活性的种族/民族差异; 4）检查唾液脂肪酶活性与邻苯二甲酸酯代谢物的尿水平的关系; 5）检查唾液脂肪酶多态性和单倍型与邻苯二甲酸酯代谢物的尿水平的关系; 6）获得关于尿中邻苯二甲酸酯单酯的葡萄糖醛酸化程度的初步数据;与流行病学项目（项目2）合作，研究脂肪酶基因型和表型与儿童发育结果的关系。双酚A：1）在我们的非裔美国人、高加索人和西班牙裔人群中对人UGT 2B 7的常见错义多态性进行基因分型，及其与尿代谢物的关联; 2）鉴定和评估我们的非裔美国人、高加索人和西班牙裔人群中人UGT 2B 7的常见启动子、编码区和剪接位点多态性，建立常见单倍型，及其与尿代谢物的关联 3）与项目2合作，检查人类UGT 2B 7基因型/单体型 对发展成果的影响。持续的PON 1表型？基因型研究：1）确定高密度脂蛋白（HDL）水平为现有的出生队列，并进行详细的基因型？表型再分析，2）PON 1多态性的扩展出生队列的基因型和单倍型新成员; 3）与项目2合作，检查PON 1基因型和表型对发育结果的影响。

Description (provided by applicant): The overall goal of this molecular genetic project is to assess gene?environment interactions that may influence individual susceptibility to the EDs and developmental neurotoxicants that are the overall scientific theme of this Center. The plan is to meet this objective by identifying and characterizing polymorphisms and variations in expression levels of PON1, lipase and UGT-glucuronosyltransferase, all involved in the metabolism and detoxification of EDs and pesticides. The specific aims of this application are, Phthalates: 1) examine salivary lipase activity as a biomarker for conversion of phthalate diesters to phthalate monoesters; 2) determine expression levels of the three linked human lipase genes in human salivary glands; 3) determine racial/ethnic differences in the frequencies of the common polymorphisms in the salivary human lipase gene(s) and in salivary lipase activity; 4) examine salivary lipase activity in relation to urinary levels of phthalate metabolites; 5) examine salivary lipase polymorphisms and haplotypes in relation to urinary levels of phthalate metabolites; 6) obtain pilot data on the extent of glucuronidation of phthalate monoesters in urine; and 7) collaborate with the epidemiology project (Project 2) to examine association of lipase genotype and phenotype with child developmental outcomes. Bisphenol A: 1) genotype the common missense polymorphism in human UGT2B7 in our population of African-Americans, Caucasians and Hispanics and its association with urinary metabolites; 2) identify and assess common promoter, coding region and splice-site polymorphisms in human UGT2B7 in our African-Americans, Caucasians and Hispanics, establish the common haplotypes, and their association with exposure; and 3) collaborate with Project 2 to examine human UGT2B7 genotype/haplotype effects on developmental outcomes. Continuing PON1 phenotype?genotype studies: 1) determine high-density lipid (HDL) levels for the existing birth cohort and carry out a detailed genotype?phenotype reanalysis, 2) genotype and haplotype new members of the extended birth cohort for PON1 polymorphisms; and 3) collaborate with Project 2 to examine PON1 genotype and phenotype effects on developmental outcomes.