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

金属采矿和冶炼业务是加拿大重要的工业和经济活动。随着在广阔但脆弱的北方生态系统中开展新的采矿项目，这些活动预计将大量增加，并向淡水环境中释放潜在的有毒微量元素。评价此类污染物对水生生物的影响的关键是开展以科学为基础的生态风险评估，将微量元素的可得性、生物累积性和毒性联系起来。由于对微量元素如何与生理上重要的生物分子产生有害的相互作用知之甚少，因此解决这一问题的研究计划具有重大意义。拟议的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。第一种方法涉及到从金属影响的环境中收集的各种水生生物的微量元素的亚细胞分配的测定。将进行这种亚细胞金属测量以区分（i）金属敏感隔室中积累的金属，其代表导致活细胞中不利影响的积累金属的比例，和（ii）解毒金属隔室中的金属。第二个互补的主题需要一个敏感的生物分子，发挥重要的生物化学和/或生理作用，但有害的目标，这些有毒的微量元素的详细表征。使用国家的最先进的多维分析方法，即联用技术，金属络合物与这种敏感的细胞内实体将被分离，鉴定和定量。这个跨学科的研究计划，涉及分析化学，生物化学，细胞生物学和毒理学方面，将集中在当前感兴趣的金属（镉，汞，砷，镍，铊和一些稀土元素）。我们还提出了一个比较的方法，在动物模型和地理纬度。在这个层次上的整合研究将大大推进我们目前的知识状态的微量金属毒性的生物生活在金属污染的水生环境。我们预计，该计划的结果将有助于环境风险评估人员改进模型的开发，以帮助他们更好地了解和预测金属毒性。拟议的研究将涉及培训学生谁将参与国家和国际合作，从其他实验室的实习中受益，并有助于在环境毒理学领域的专业知识和知识。

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.