Project 4: Neurobehavioral and bioenergetic consequences of evolving resistance to polycyclic aromatic hydrocarbons in a multi-stressor environment

摘要 杜克大学超级基金研究中心(DUSRC)的首要目标是确定未来的生活后果 早年接触多环芳烃(PAHs)和重金属的风险。根据《公约》 超级基金关于了解暴露于危险物质的流行病学和生态影响的任务 化学品，DUSRC-项目4解决进化过程中多环芳烃和金属暴露的生态后果 毒物学背景。对危险污染物的进化抵抗力对 环境健康、生态风险评估和管理。然而，我们的关键知识差距仍然存在 了解污染适应和健康后果的机制，特别是当动物 暴露在多种化学物质(同时或顺序)和其他非生物应激源的自然环境中 环境。为了解决这些差距，我们扩展了我们之前对多环芳烃进化抗性的广泛研究 在弗吉尼亚州伊丽莎白河(ER)的大西洋千里鱼(Fundulus)异地叉尾鱼群，朝着一个新的方向发展。具体来说，我们将 阐明线粒体作为多环芳烃和金属在早期发育过程中的重要作用 在以后的生活和后代中调解不良的行为和生物能量后果 最佳和次佳的热氧和溶解氧条件。我们的具体目标是：目标1--确定 早年同时接触多环芳烃、镉和铅对晚年生活健康的影响；目的2-阐明 发育过程中暴露于多环芳烃和随后的镉对晚年生活和跨代健康的影响 或铅暴露，并确定与表观遗传修饰的联系；目标3-比较肠道微生物组 抗多环芳烃鱼类和敏感鱼类的差异，并阐明肠道微生物群的潜在贡献 利用无菌剑鱼研究多环芳烃的抗性目标4-发展生态效应导向分析 基于中通量线粒体和行为分析来评估环境样品的毒性 包括在DUSRC-Project 5中提取的补救样本。此外，我们将与 项目2(行为研究)和项目3(线粒体研究)，侧重于实验设计方面 和毒性机制。我们亦会与社区参与核心紧密合作，推广 我们的研究成果以相关社区、数据管理为核心进行实验设计、数据管理 和分析，以及化学分析的分析化学核心。该项目将大力参与 培训研究生和博士后研究人员，并将与培训核心协调活动 以及用于整体支持和研究翻译的管理核心。总体而言，研究将从生态角度阐明 多环芳烃和金属暴露的相关适合性结果以及潜在分子的选定方面 机制，同时呈现的毒性测试，以表征有效性 补救措施。新的研究领域包括阐明多环芳烃和金属的交互作用，辨别其作用 肠道微生物群在多环芳烃抗性中的作用，并开发一种与生态相关的毒性分析 以杀人鱼行为和能量学为目标的任务3，为生态风险评估提供信息。

Abstract The overarching goal of the Duke Superfund Research Center (DUSRC) is to determine later life consequences of early life exposure to polycyclic aromatic hydrocarbons (PAHs) and heavy metals. In accordance with the Superfund Mandate on understanding epidemiological and ecological impacts of exposure to hazardous chemicals, DUSRC-Project 4 addresses ecological outcomes of PAH and metal exposure in an evolutionary toxicology context. Evolved resistance to hazardous contaminants has far reaching implications for environmental health, ecological risk assessment, and management. However, key knowledge gaps exist in our understanding of the mechanisms of pollution adaptation and fitness consequences, especially when animals are exposed to multiple chemicals (simultaneous or sequential) and other abiotic stressors in their natural environment. Addressing these gaps, we extend our extensive previous research on evolved resistance to PAHs in Atlantic killifish Fundulus heteroclitus in the Elizabeth River (ER), VA, in a new direction. Specifically, we will elucidate the role of mitochondria as an important target of PAHs and metals during early development in mediating adverse behavioral and bioenergetic outcomes later in life and in subsequent generations under optimal and suboptimal thermal and dissolved oxygen conditions. Our specific aims are: Aim 1 – to determine later life fitness consequences of early life simultaneous exposures to PAHs and Cd and Pb; Aim 2 – to elucidate later life and cross generational fitness consequences of developmental exposures to PAHs and subsequent Cd or Pb exposure and determine links to epigenetic modifications; Aim 3 – to compare the gut microbiome differences in PAH-resistant and sensitive fish, and elucidate the potential contributions of the gut microbiome on PAH resistance using germ-free killifish studies; Aim 4 – to develop an ecological-effect directed analysis based on medium-throughput mitochondrial and behavioral assays to assess toxicity of environmental samples including remediated samples derived in DUSRC-Project 5. Moreover, we will bi-directionally collaborate with Project 2 (behavioral studies) and Project 3 (mitochondrial studies), focusing on aspects of experimental design and toxicity mechanisms. We will also work closely with the community engagement core for dissemination of our findings to the relevant communities, the data management core for experimental design, data management and analyses, and the analytical chemistry core for chemical analyses. The project will be heavily involved in the training of graduate students and post-doctoral researchers and will coordinate activities with the training core as well as the admin core for overall support and research translation. Overall, studies will elucidate ecologically relevant fitness outcomes of PAH and metal exposures and selected aspects of underlying molecular mechanisms in killifish populations, while rendering the toxicity assays for characterizing effectiveness of remediation. Novel areas of research include elucidating PAH and metal interactive effects, discerning the role of the gut microbiome in PAH resistance, and developing an ecologically relevant toxicity analyses based on killifish behavior and energetics that target Mandate 3 to inform ecological risk assessment.