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

金属开采和冶炼业务是加拿大一项重要的工业和经济活动。这些活动预计将随着在辽阔但脆弱的北部生态系统进行新的采矿项目而大幅增加，向淡水环境中释放潜在的有毒微量元素。评估这类污染物对水生生物的影响的一个关键是制定以科学为基础的生态风险评估(ERA)，该评估将微量元素的有效性、生物积累和毒性联系起来。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的相互作用知之甚少，因此针对这一主题的研究计划具有重要意义。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，并阐明这种影响的生化后果。拟议的研究将在新兴的环境金属学领域使用两种创新方法。第一种方法涉及确定从金属冲击环境中收集的各种水生生物中微量元素的亚细胞分配。这种亚细胞金属测量将被用于区分(I)金属敏感隔室中积累的金属，这代表了在活细胞中造成不利影响的累积金属的比例，以及(Ii)解毒金属隔室中的金属。第二个补充主题需要详细描述敏感生物分子的特征，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靶标。使用最先进的多维分析方法，即联用技术，将分离、鉴定和量化具有这种敏感细胞内实体的金属络合物。这一跨学科研究计划涉及分析化学、生物化学、细胞生物学和毒理学，将重点关注当前感兴趣的金属(Cd、Hg、As、Ni、Tl和一些稀土元素)。我们还提出了在动物模型和地理纬度方面的比较方法。这种综合水平的研究将极大地提高我们对生活在被金属污染的水环境中的生物中痕量金属毒性的了解现状。我们预计，该项目的结果将有助于为环境风险评估人员开发改进的模型，以帮助他们更好地了解和预测金属毒性。拟议的研究将包括培训学生，这些学生将参加国家和国际合作，从其他实验室的实习中受益，并为环境毒理学领域的专门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.