Developmental VOC Exposure in Zebrafish: Toxic Mechanisms and Biomarkers

摘要/摘要： 人为挥发性有机化合物(VOCs)已成为高度重视的环境问题 通过工业废气、燃料精炼厂和汽车尾气无处不在的城市暴露造成的污染物，如 以及估计78%的超级基金网站的挥发性有机化合物污染。城市地区的居民 由于室内蒸汽侵入、自来水、摄入受污染的水而不成比例地暴露于VOCs 鱼，以及环境中的户外暴露。室内和室外的吸入、摄取和皮肤吸收 污染源是人类暴露的途径，处于危险中的社区往往长期暴露在复杂的环境中 挥发性有机化合物的混合物。与VOC暴露相关的各种不良健康影响涉及呼吸系统、 心血管、肾脏、肝脏、内分泌、免疫和神经系统。研究还表明 孕妇长期接触VOC与出生缺陷和早产有关。尽管如此，这些健康风险 仍然没有明确的定义。环境意识和研究领导中心(Clear)寻求 减少环境污染物对公众和环境健康的影响，重点是 底特律令人震惊的早产率。我们的假设是，接触与环境相关的VOCs 浓度和混合物将损害斑马鱼的发育、免疫功能和生殖健康，以及 美国国立卫生研究院接受的模式生物。创新、高通量技术的开发将使 Clear B1团队执行新的发育、生殖、神经行为、免疫和多代 评估暴露于六种不同浓度挥发性有机化合物的不良表型效应的生物测定(目标1)， 同样，确定接触VOC混合物的影响(目标2)，并使用分子技术来确定 转录和表观遗传途径，以及与挥发性有机化合物相关的潜在生物标记物的排名(根据敏感性) 暴露和特定生物效应(目标3)。使用来自项目E1、E2、B3和CEC的数据，我们将重点关注 我们对与环境相关的VOC浓度和混合物的实验在底特律和已知 超级基金网站。这项拟议的研究具有重要意义，因为其结果有望填补知识空白 在基础和应用领域，并通过扩大我们的深度，产生积极的翻译影响 了解单个VOCs和VOC混合物对健康的影响，这是关键的发展窗口 对于这些不利的健康影响和影响的生物标记物，以及环境影响的机制， 成人发病和多代疾病。这些结果将与研究培训、数据共享 分析和化学分析核心，以推动循证战略的发展，以预防和 治疗环境引起的疾病。最终，这些策略将被社区参与使用 核心是制定VOC预防和干预措施，以改善妇女和儿童的健康 底特律(图1)。

Summary/Abstract: Anthropogenic Volatile Organic Compounds (VOCs) have emerged as high priority environmental contaminants due to ubiquitous urban exposure via industrial exhaust, fuel refineries, and vehicle exhaust, as well as VOC contamination at an estimated 78% of Superfund sites. Residents in urban areas are disproportionately exposed to VOCs as a result of indoor vapor intrusion, tap water, ingestion of contaminated fish, and ambient outdoor exposure. Inhalation, ingestion, and dermal adsorption from indoor and outdoor sources are routes for human exposure, and at-risk communities are often chronically exposed to complex mixtures of VOCs. Varied adverse health impacts associated with VOC exposure involve the respiratory, cardiovascular, renal, hepatic, endocrine, immune, and nervous systems. Studies also suggest that chronic, maternal VOC exposure is linked to birth defects and preterm birth. Nonetheless, these health risks remain ill-defined. The Center for Leadership in Environmental Awareness and Research (CLEAR) seeks to reduce the impacts of environmental contaminants on both public and environmental health, focusing on the alarming rate of preterm births in Detroit. Our hypothesis is that exposure to VOCs at environmentally-relevant concentrations and mixtures will impair development, immune function, and reproductive health in zebrafish, an NIH-accepted model organism. The development of innovative, high-throughput techniques will enable the CLEAR B1 team to perform novel developmental, reproductive, neurobehavioral, immune, and multigenerational bioassays to evaluate adverse phenotypic effects of exposure to six VOCs at various concentrations (Aim 1), similarly, identify effects of exposure to VOC mixtures (Aim 2), and employ molecular techniques to identify transcriptomic and epigenetic pathways, as well as rank potential biomarkers (by sensitivity), relevant to VOC exposure and specific biological effects (Aim 3). Using data from Projects E1, E2, B3, and the CEC, we will focus our experiments on environmentally-relevant VOC concentrations and mixtures found in Detroit and at known Superfund sites. The proposed research is significant because the results are expected to fill knowledge gaps in the field at basic and applied levels and have a positive translational impact by expanding the depth of our understanding regarding health impacts of individual VOCs and VOC mixtures, critical developmental windows for these adverse health impacts and biomarkers of effect, and mechanisms for environmentally-influenced, adult-onset and multigenerational disease. These results will be shared with the research training, data analysis, and chemical analysis cores to advance the development of evidence-based strategies to prevent and treat environmentally-induced disease. Ultimately, these strategies will be used by the community engagement core to enact VOC prevention and intervention measures to improve the health of mothers and children in Detroit (Figure 1).