Molecular insights into the toxicology of trace elements in aquatic organisms using metallomic approaches

金属采矿和冶炼作业是加拿大重要的工业和经济活动。这些活动预计将随着广阔但脆弱的北部生态系统中的新采矿项目而显着增加，并将潜在有毒的微量元素释放到淡水环境中。评估此类污染物对水生生物影响的关键是开发基于科学的生态风险评估 (ERA)，它将微量元素的可用性、生物蓄积性和毒性联系起来。由于人们对微量元素如何与生理上重要的生物分子产生有害相互作用知之甚少，因此针对这一主题的研究计划非常重要。拟议研究计划的长期目标是了解微量元素如何在分子和细胞水平上发挥其毒性作用，并阐明这种作用的生化后果。拟议的研究将在环境金属学的新兴领域使用两种创新方法。第一种方法涉及测定从受金属影响的环境中收集的各种水生生物中微量元素的亚细胞分配。将进行此类亚细胞金属测量，以区分（i）金属敏感区室中积累的金属（代表对活细胞产生不利影响的积累金属的比例）和（ii）解毒金属区室中的金属。第二个补充主题需要对敏感生物分子进行详细表征，这些生物分子发挥着重要的生化和/或生理作用，但却是这些有毒微量元素的有害目标。使用最先进的多维分析方法，即联用技术，将分离、鉴定和量化具有此类敏感细胞内实体的金属络合物。这个跨学科研究项目涉及分析化学、生物化学、细胞生物学和毒理学等方面，将重点关注当前感兴趣的金属（镉、汞、砷、镍、铊和一些稀土元素）。我们还提出了动物模型和地理纬度方面的比较方法。这种整合水平的研究将极大地推进我们对生活在金属污染水生环境中的生物体中痕量金属毒性的了解。我们预计该计划的结果将有助于开发环境风险评估人员改进的模型，帮助他们更好地了解和预测金属毒性。拟议的研究将涉及对学生的培训，他们将参与国内和国际合作，从其他实验室的实习中受益，并为环境毒理学领域的专业知识和知识做出贡献。

Metal mining and smelting operations represent an important industrial and economic activity in Canada. These activities, which are expected to significantly increase with new mining projects in the vast but fragile northern ecosystems, release potentially toxic trace elements into freshwater environments. A key to the evaluation of the effects of such contaminants on aquatic organisms is the development of science-based ecological risk assessments (ERA), which link availability, bioaccumulation and toxicity of trace elements. Since little is known about how trace elements exert deleterious interactions with physiologically important biomolecules, a research program addressing this subject is of major importance. The long-term objective of the proposed research program is to understand how trace elements exert their toxic effects, at the molecular and cellular levels, and to elucidate the biochemical consequences of such effects. The proposed research will use two innovative approaches in the emerging area of environmental metallomic. The first approach involves the determination of the subcellular partitioning of trace elements in various aquatic organisms collected from metal-impacted environments. Such subcellular metal measurements will be performed to discriminate between (i) metals accumulated in the metal-sensitive compartment, which represents the proportion of accumulated metals responsible for adverse effects in living cells, and (ii) metals in the detoxified-metal compartment. The second complementary theme entails a detailed characterization of the sensitive biomolecules that play important biochemical and/or physiological roles, but are harmfully targeted by these toxic trace elements. Using state-of-the-art multidimensional analytical approaches, namely hyphenated techniques, metal complexes with such sensitive intracellular entities will be isolated, identified and quantified. This interdisciplinary research program, involving aspects of analytical chemistry, biochemistry, cellular biology and toxicology, will focus on metals of current interest (Cd, Hg, As, Ni, Tl and some rare earth elements). We also propose a comparative approach in terms of animal models and of geographical latitudes. Research at this level of integration will greatly advance our current state of knowledge of trace metal toxicity in organisms living in metal-contaminated aquatic environments. We anticipate that the results from this program will contribute to the development of improved models for environmental risk assessors to help them better understand and predict metal toxicity. The proposed research will involve training of students who will participate in national and international collaborations, benefit from internships in other labs and contribute to the expertise and knowledge in the field of environmental toxicology.