Developmental VOC Exposure in Zebrafish: Toxic Mechanisms and Biomarkers

总结/摘要： 人为挥发性有机化合物（VOCs）已成为高度优先的环境问题， 污染物，由于无处不在的城市暴露通过工业废气，燃料精炼厂，和汽车尾气， 以及挥发性有机化合物污染的估计78%的超级基金网站。城市居民 由于室内蒸汽侵入、自来水、摄入受污染的 鱼和环境户外暴露。室内和室外的吸入、摄入和皮肤吸收 污染源是人类接触的途径，处于风险中的社区往往长期接触复杂的 VOC的混合物。与挥发性有机化合物接触相关的各种不利健康影响涉及呼吸系统， 心血管、肾、肝、内分泌、免疫和神经系统。研究还表明 母亲长期接触VOC与出生缺陷和早产有关。然而，这些健康风险 仍然不明确。环境意识和研究领导中心（CLEAR）旨在 减少环境污染物对公众和环境健康的影响，重点是 底特律的早产率惊人我们的假设是，在环境相关的VOC暴露 浓度和混合物将损害斑马鱼的发育，免疫功能和生殖健康， NIH认可的模式生物。创新的高通量技术的发展将使 CLEAR B1团队将执行新的发育，生殖，神经行为，免疫和多代 生物测定法，以评估暴露于不同浓度的六种挥发性有机化合物的不良表型效应（目标1）， 同样，确定暴露于VOC混合物的影响（目标2），并采用分子技术来确定 转录组学和表观遗传学途径，以及潜在的生物标志物排名（按灵敏度），与VOC相关 暴露和特定生物效应（目标3）。利用项目E1、E2、B3和CEC的数据，我们将重点关注 我们的实验对环境相关的挥发性有机化合物浓度和混合物发现在底特律和已知的 超级基金网站。拟议的研究意义重大，因为其结果有望填补知识空白 在该领域的基础和应用水平，并通过扩大我们的深度， 了解单个VOC和VOC混合物对健康的影响，关键发展窗口 对于这些不利的健康影响和生物标志物的影响，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，以推进循证战略的发展， 治疗环境引起的疾病。最终，这些策略将被社区参与所使用。 核心是制定挥发性有机化合物预防和干预措施，以改善母婴健康， 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).