Gene-Environment Interactions Causing Differential Susceptibility to Chemical Exposure in High-Throughput Screening

摘要 暴露在环境化学物质中与癌症发病率增加、出生缺陷、 认知发展和神经退行性疾病。不幸的是，不断扩大的差距 环境中的化学品数量及其潜在健康危害的数据继续扩大。 尽管使用体外技术的最新进展，高通量筛选(HTS)技术可能会加快 化学测试的速度，这些平台无法检测到只能在系统性检查中诊断的不良健康影响 水平，如发育异常或异常行为。此外，还需要活体环境来 量化个体间遗传变异对发育迟缓易感性差异的贡献 暴露的行为后果。有强有力的证据表明，基因-环境相互作用(GxE) 与个体遗传变异有关的因素在健康结果中起着重要作用，这些相互作用是 可能是对化学物质暴露的异质性的主要来源。因此，理解 GxE对化学品暴露的不同易感性将是保护公众健康的关键。我们建议 开发一个协作式生物信息学+实验系统来研究 基因-环境相互作用(Y=GxE)，全面描述(Y)，细化(E)的表征， 然后对(G)进行调查和探索。该系统将利用化学品HTS产生的海量数据 通过对斑马鱼胚胎关键期(前5天)的形态和行为分析 在受精后立即)，当发育过程在 脊椎动物模式生物和人类。将对这些数据进行分析，以量化导致差异的GxE 化学品暴露后的健康后果。这项提议的持久意义将是一个可扩展的、 快速解决对不断膨胀的化学品的差异遗传易感性问题的高效系统 宇宙。

ABSTRACT Exposure to environmental chemicals has been linked to increases in cancer incidence, birth defects, impaired cognitive development, and neurodegenerative disease. Unfortunately, the gap between the ever-expanding number of chemicals in the environment and data on their potential health hazards continues to widen. Although recent advancements that use in vitro, high-throughput screening (HTS) technologies may speed the pace of chemical testing, those platforms cannot detect adverse health effects diagnosable only at a systemic level, such as abnormal development or aberrant behavior. Additionally, an in vivo context is needed to quantify the contribution of interindividual genetic variation to susceptibility differences in developmental or behavioral consequences of exposure. There is strong evidence that gene-environment interactions (GxE) related to individual genetic variation play an important role in health outcomes, and that these interactions are likely a major source of the heterogeneity in response to chemical exposure. Thus, understanding the role of GxE in differential susceptibility to chemical exposure will be key to protecting public health. We propose development of a collaborative bioinformatic + experimental system to study health outcomes affected by gene-environment interactions (Y=GxE) that comprehensively describes (Y), refines characterization of (E), then investigates and probes (G). This system will leverage massive data generated by HTS of chemicals through morphological and behavioral assays in embryonic zebrafish during the critical period (the first 5 days immediately after fertilization) when developmental processes are most highly-conserved between this vertebrate model organism and humans. These data will be analyzed to quantify GxE that elicit differential health outcomes following chemical exposure. The lasting significance of this proposal will be a scalable, efficient system to rapidly address questions of differential genetic susceptibility to an expanding chemical universe.