Gene-dioxin interaction and low birth weight in a highly exposed European cohort

高度暴露的欧洲队列中的基因-二恶英相互作用和低出生体重

基本信息

批准号：
9050541
负责人：
Jennifer Lisa Ames
金额：
$ 3.82万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2019-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9050541
关键词：
AHR gene Affect Age Animals Archives Area Aryl Hydrocarbon Receptor Birth Blood Blood coagulation Blood specimen Body Burden Breast Feeding CYP1A1 gene CYP1B1 gene Cancer Etiology Cell Death Chemical Exposure Chemicals Child Child health care Chlorinated Hydrocarbons Cohort Studies Conflict (Psychology)Cytochromes DNA Data Data Quality Dioxins Disease Endocrine Disruptors Endocrine disruption Enrollment Environment Environmental Risk Factor Enzymes Epidemiology Etiology European Explosion Exposure to Female Fetal Development Fetal Diseases Fetal Growth Fetal Growth Retardation Future Generations Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genotype Half-Life Health Hormones Human Human Activities Human body Individual Industrial Accidents Intervention Investigation Italy Life Life Cycle Stages Link Low Birth Weight Infant Malignant Neoplasms Measurement Measures Metabolism Morbidity - disease rate Mothers Newborn Infant Outcome Participant Pathway interactions Perinatal Exposure Plants Poison Polychlorinated Biphenyls Population Predisposition Pregnancy Proteins Recording of previous events Recruitment Activity Regulatory Pathway Reproduction Research Risk Sampling Serum Shapes Single Nucleotide Polymorphism Subgroup Time Tissues Toxic effect Variant Woman Women&apos s Health Xenobiotics aged base cell growth cohort fetal fetal dioxin exposure fetal programming follow-up gene environment interaction genetic association genetic makeup genetic variant high risk in utero insight maternal cigarette smoking maternal serum mortality offspring persistent organic pollutants prenatal public health relevance risk variant transcription factor

项目摘要

DESCRIPTION (provided by applicant): Although increasing animal evidence supports the hypothesis that in utero exposure to endocrine disrupting compounds can have a long-term impact on the health of the 2nd and subsequent generations, the evidence in humans is nearly non-existent. In addition, individuals may have differences in susceptibility to chemical exposure based on their genetic make-up. We propose to study genetic susceptibility in a unique population of children whose mothers, participants of the Seveso Women's Health Study (SWHS), were exposed to one of the most potent endocrine disruptors, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin). On July 10, 1976, an explosion at a chemical plant near Seveso, Italy resulted in a toxic plume that exposed nearby residents to high levels of TCDD. The SWHS, a retrospective cohort study, was initiated in 1996, to investigate the health of 981 women who were newborn to age 40 years in 1976, had resided in the immediate vicinity of the plant, and had archived samples of blood collected soon after the explosion. The SWHS is the only comprehensive study of health effects of TCDD exposure in a female population, and has the unique benefit of measurements of individual-level TCDD in blood collected near the time of the explosion. We are currently re-contacting SWHS women to enroll ~955 children aged 0-38 years in a study of their health, to determine whether in utero TCDD exposure is associated with health outcomes at birth or later in life. The proposed study will use DNA from blood collected during the current (2014-2016) follow up to genotype mother-child pairs in the aryl hydrocarbon receptor (gene: AhR, protein: AhR) pathway, an enzymatic network that directs the metabolism of TCDD and other xenobiotics in humans. We will conduct a gene-by- environment (GxE) analysis to evaluate the modifying effect of genetic polymorphisms in the AhR pathway on susceptibility to dioxin toxicity in women and their children born after the explosion. In particular, we will use longitudinal measurements of serum TCDD (1976 and 1996) to examine differences in TCDD metabolism across genetic subgroups of the SWHS (Aim 1). We will then use genotype data on mother-child pairs in AhR pathway genes to examine interaction between the maternal and child genotypes with in utero dioxin exposure on birthweight in children born after the explosion. With its targeted focus on the AhR pathway, this study is uniquely equipped to examine the influence of genotype on dioxin half-life longitudinally and the first study of how both maternal and child genetics may shape fetal susceptibilities to dioxin.

描述（由申请人提供）：尽管越来越多的动物证据支持这样的假设：在子宫内暴露于内分泌干扰化合物会对第二代及后代的健康产生长期影响，但在人类中几乎不存在证据。此外，根据其基因构成，个体对化学物质暴露的易感性可能存在差异。我们建议研究其母亲是塞维索妇女健康研究参与者的独特儿童群体的遗传易感性。 1976 年 7 月 10 日，意大利塞维索附近的一家化工厂发生爆炸，这是一种最有效的内分泌干扰物 2,3,7,8-四氯二苯并-对二恶英（TCDD 或二恶英）。 SWHS 是一项回顾性队列研究，于 1996 年启动，旨在调查 981 名妇女的健康状况。她们出生于 1976 年，年龄在 40 岁以下，居住在工厂附近，并在爆炸后不久对采集的血液样本进行了存档。SWHS 是唯一一项针对女性人群接触 TCDD 健康影响的综合研究，具有在爆炸发生时采集的血液中测量个体水平 TCDD 的独特优势。我们目前正在重新联系 SWHS 妇女，招募约 955 名 0-38 岁的儿童进行健康研究。以确定子宫内 TCDD 暴露是否与出生时或以后的健康结果相关。拟议的研究将使用当前（2014-2016 年）随访期间收集的血液 DNA，对芳基碳氢化合物受体中的母子对进行基因分型。基因：AhR，蛋白质：AhR）途径，一种指导人类 TCDD 和其他外源物质代谢的酶网络。我们将进行基因环境（GxE）分析来评估修饰。 AhR 通路中的基因多态性对爆炸后出生的妇女及其子女对二恶英毒性的易感性的影响特别是，我们将使用血清 TCDD（1976 年和 1996 年）的纵向测量来检查跨遗传亚组的 TCDD 代谢差异。 SWHS（目标 1）然后，我们将使用 AhR 途径基因中母子对的基因型数据来检查母子基因型与子宫内二恶英暴露之间的相互作用。这项研究以 AhR 途径为目标，具有独特的能力，可以纵向研究基因型对二恶英半衰期的影响，也是首次研究母体和遗传儿童如何影响胎儿对二恶英的易感性。二恶英。