Genetic and Epigenetic Determinants of Sensitivity to Polycyclic Aromatic Hydrocarbons in Birds

鸟类对多环芳烃敏感性的遗传和表观遗传决定因素

• 批准号: RGPIN-2021-03037
• 负责人: Head, Jessica
• 金额: $ 2.91万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742342
• 关键词: Genetic; Epigenetic; Determinants; Sensitivity; Polycyclic

Risk assessment for environmental contaminants in wildlife depends on extrapolating toxicity data from a small number of model organisms to tens of thousands of species of concern. This is widely acknowledged to be problematic given that sensitivity to contaminants can vary by orders of magnitude across species and even among individuals. The long-term objective of my research program is to advance understanding of variation in sensitivity to environmental contaminants among species and individuals. This objective stems from the insight that variable responses can be used to resolve fundamental questions about mechanism of action of toxicants, and that knowledge gained can be applied to meet the grand challenge of assessing chemical risk in the face of abundant variation in the natural world. My proposed research program focusses on the effects of polycyclic aromatic hydrocarbons (PAHs) in avian embryos. PAHs are contaminants of concern in the Canadian environment, and have been studied extensively in aquatic organisms such as fish, but relatively few data are available for birds. The avian embryo is an excellent model for experimental studies because the egg is a closed system, minimally affected by environmental signals during development (unlike fish and mammals). I have chosen to focus on three species of birds that are established models in the field of ecotoxicology and for which we have developed toxicogenomic tools; two domestic species, chicken (Gallus gallus), and Japanese quail (Coturnix japonica) and a wild species, double-crested cormorant (Phalacrocorax auritus). Critically, my recent work on these species has established that they are differentially sensitive to PAHs. In addition to being topical, PAHs are a good choice for my research program because they interact with a well-described molecular pathway - the aryl hydrocarbon receptor (AHR) signaling pathway - permitting deeper mechanistic investigations. My previous research identified a strong genetic component to species sensitivity related to AHR signaling, but it is currently unclear how these findings apply to PAHs. Aims 1 and 2 of the proposed research will resolve this knowledge gap and explore additional questions relating to gene expression and toxicokinetics, as well as differences in sensitivity among individuals. In Aim 3 we will take the innovative step of focusing on epigenetic determinants of sensitivity. Epigenetics refers to a layer of information in cells that is heritable as the cell divides but is not associated with the genetic sequence itself. Epigenetic marks can contribute to variability, but have seldom been investigated in the context of sensitivity to contaminants. Building on my contributions to established knowledge about genetic determinants of sensitivity to AHR ligands in birds, and our recent progress on epigenetic determinants, we are poised to make significant breakthroughs in the next 5 years.

对野生动物中环境污染物的风险评估取决于从少数模式生物到数万个受关注物种的毒性数据。这被广泛认为是有问题的，因为对污染物的敏感性在物种之间甚至在个体之间可能会有数量级的差异。我的研究计划的长期目标是促进物种和个体之间对环境污染物敏感性变化的理解。这一目标源于这样一种认识，即可变响应可用于解决有关毒物作用机制的基本问题，所获得的知识可用于应对在自然界存在丰富变化的情况下评估化学品风险的巨大挑战。我提议的研究计划重点关注多环芳烃（PAHs）对鸟类胚胎的影响。多环芳烃是加拿大环境中令人关注的污染物，已在鱼类等水生生物中进行了广泛研究，但鸟类的数据相对较少。鸟类胚胎是实验研究的一个很好的模型，因为鸡蛋是一个封闭的系统，在发育过程中受环境信号的影响最小（不像鱼类和哺乳动物）。我选择专注于三个物种的鸟类，建立在生态毒理学领域的模型，我们已经开发了toxicgenomic工具;两个国内物种，鸡（原鸡），日本鹌鹑（Coturnix japonica）和野生物种，双冠鸬鹚（Phalacrocorax auritus）。重要的是，我最近对这些物种的研究已经确定它们对多环芳烃的敏感性不同。 除了是热门话题，多环芳烃是我的研究计划的一个很好的选择，因为他们与一个良好的描述分子途径-芳烃受体（AHR）信号通路-允许更深入的机制研究相互作用。我以前的研究确定了与AHR信号相关的物种敏感性的强烈遗传成分，但目前还不清楚这些发现如何适用于多环芳烃。拟议研究的目标1和2将解决这一知识差距，并探索与基因表达和毒理学相关的其他问题，以及个体之间的敏感性差异。在目标3中，我们将采取创新的步骤，重点关注敏感性的表观遗传决定因素。表观遗传学是指细胞中的一层信息，随着细胞分裂而遗传，但与遗传序列本身无关。表观遗传标记可以有助于变异性，但很少在对污染物敏感性的背景下进行研究。基于我对鸟类对AHR配体敏感性的遗传决定因素的已有知识的贡献，以及我们最近在表观遗传决定因素方面的进展，我们准备在未来5年内取得重大突破。