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

• 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
• 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' 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

 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(申请人提供)：尽管越来越多的动物证据支持这样一种假设，即在子宫内暴露于内分泌干扰性化合物会对第二代和后代人的健康产生长期影响，但在人类身上几乎没有证据。此外，个体对化学物质暴露的易感性可能因其基因构成而有所不同。我们建议研究一组特殊儿童的遗传易感性，这些儿童的母亲是塞维索妇女健康研究(SWHS)的参与者，他们的母亲接触到最有效的内分泌干扰物之一--2，3，7，8-四氯二苯并-对二恶英(TCDD或二恶英)。1976年7月10日，意大利塞维索附近的一家化工厂发生爆炸，导致附近居民接触到高浓度的TCDD。SWHS是一项追溯性队列研究，始于1996年，目的是调查981名1976年出生至40岁的妇女的健康状况，她们住在核电站附近，并在爆炸后不久收集了血液样本。SWHS是唯一一项关于接触TCDD对女性人群健康影响的综合研究，具有测量爆炸发生时采集的血液中个人水平TCDD的独特好处。我们目前正在重新联系SWHS妇女，让大约955名0-38岁的儿童参加一项关于她们健康的研究，以确定宫内接触TCDD是否与出生时或以后的健康结局有关。这项拟议的研究将使用在当前(2014-2016)后续行动中从血液中收集的DNA，以跟踪芳烃受体(基因：AHR，蛋白质：AHR)途径中的基因母子对，该途径是一个酶网络，指导TCDD和其他外源物质在人类中的代谢。我们将进行环境基因(GxE)分析，以评估AhR途径中的基因多态对爆炸后出生的妇女及其子女对二恶英毒性易感性的修改效果。特别是，我们将使用血清TCDD的纵向测量(1976和1996)来检查SWHS遗传亚组之间TCDD代谢的差异(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宫内二恶英暴露对爆炸后出生的儿童出生体重的交互作用。这项研究的目标是AhR途径，这项研究独特地纵向考察了基因对二恶英半衰期的影响，并首次研究了母子遗传如何影响胎儿对二恶英的易感性。