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

 描述（由申请方提供）：尽管越来越多的动物证据支持子宫内暴露于内分泌干扰化合物可能对第二代及后代的健康产生长期影响的假设，但人类中的证据几乎不存在。此外，个人对化学品接触的敏感性可能因其基因组成而有所不同。我们建议研究一个独特的儿童群体的遗传易感性，他们的母亲是Seveso妇女健康研究（SWHS）的参与者，暴露于最有效的内分泌干扰物之一，2，3，7，8-四氯二苯并-p-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，导致有毒烟雾，使附近居民暴露在高浓度的TCDD中。SWHS是一项回顾性队列研究，于1996年启动，旨在调查1976年出生至40岁的981名妇女的健康状况，这些妇女居住在工厂附近，并在爆炸后不久收集了存档的血液样本。SWHS是唯一一项全面研究TCDD暴露对女性健康影响的研究，具有独特的优势，可以测量在爆炸发生时收集的血液中的个人水平TCDD。我们目前正在重新联系SWHS妇女，招募约955名0-38岁的儿童参加他们的健康研究，以确定子宫内TCDD暴露是否与出生时或以后的健康结果有关。 这项拟议的研究将使用当前（2014-2016）随访期间收集的血液中的DNA，对芳烃受体（基因：AhR，蛋白质：AhR）途径中的母子对进行基因分型，这是一种指导人类TCDD和其他外源性物质代谢的酶网络。我们将进行基因环境（GxE）分析，以评估AhR途径中的遗传多态性对爆炸后出生的妇女及其子女对二恶英毒性敏感性的修饰作用。特别是，我们将使用纵向测量血清TCDD（1976年和1996年），以检查跨遗传亚组的SWHS（目标1）的TCDD代谢的差异。然后，我们将使用AhR途径基因中母子对的基因型数据来研究爆炸后出生的儿童中母体和儿童基因型与宫内二恶英暴露对出生体重的相互作用。随着其有针对性的重点AhR途径，这项研究是唯一配备检查基因型对二恶英半衰期的影响纵向和第一次研究如何母亲和儿童的遗传学可能塑造胎儿的易感性二恶英。

 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.