Mechanisms of developmental toxicity and metabolic disruption in fishes exposed to selenium

硒（Se）是一种必需的微量元素，在必需剂量和有毒剂量之间的差距很小，特别是在鱼类中。在加拿大和全球范围内，各种工业、农业和市政实践导致淡水生态系统中硒的负荷增加。因此，包括加拿大在内的许多国家目前正在修订其硒管理政策，以确保对鱼类种群的保护。*******众所周知，硒是一种强大的发育毒性物质，在暴露于高硒饮食中的成年雌性鱼的后代中，会导致严重的眼睛、头盖骨、脊柱和其他解剖结构的畸形。我们小组最近的工作也表明，硒暴露升高会导致鱼类的几个内分泌系统受到破坏，这些内分泌系统涉及能量稳态、有氧代谢、生理应激和繁殖。然而，这种内分泌干扰的潜在生化机制尚不清楚，更好地了解这些作用模式将为制定水质政策以保护鱼类种群和水生生态系统健康的监管者提供信息。*******这项拟议研究的总体目标是确定鱼类硒暴露引起的发育毒性和代谢破坏的机制。我们将采用综合方法，结合分子、生化、药理学和行为技术来实现这一目标。为了验证硒引起的早期生命发育毒性是由氧化应激引起的假设（目的1），我们将使用在存在和不存在抗氧化防御诱导性和抑制剂的情况下暴露于硒的斑马鱼胚胎，然后测定基因表达、氧化应激标记物和孵化鱼苗的畸形。为了验证鱼类膳食硒暴露会导致类似人类II型糖尿病的不良代谢综合征的假设（目的2），我们将使用斑马鱼和虹鳟鱼来确定对调节能量稳态和有氧代谢的关键中间代谢过程的影响。为了验证硒暴露导致鱼类视觉系统损伤的假设（目的3），我们将使用斑马鱼来确定参与眼睛发育的关键基因的表达，眼睛结构的组织病理学，以及通过几种行为分析提供的功能齐全的视觉系统的证据的功能反应。*******总的来说，这些创新的综合实验将增加我们对与环境相关的硒暴露相关的毒理学反应的机制理解，这可能适用于显示常见病因的其他类别的水生污染物。这项研究计划的目标与我的长期研究目标密切相关，我的长期研究目标是研究暴露于优先水生污染物的鱼类的发育和生殖毒性机制。******

Selenium (Se) is an essential trace element with a narrow margin between required and toxic doses, particularly in fishes. A variety of industrial, agricultural, and municipal practices in Canada and globally result in increased loading of Se into freshwater ecosystems. As a result, many countries, including Canada, are currently revising their regulatory policies for Se to ensure the protection of fish populations.*******It is well-known that Se is a potent developmental toxicant, causing severe deformities of the eye, cranium, spine, and other anatomical structures in offspring of adult female fish exposed to elevated dietary Se. Recent work by our group has also demonstrated that elevated Se exposure causes disruption of several endocrine systems in fishes that are involved in energy homeostasis, aerobic metabolism, physiological stress, and reproduction. However, the underlying biochemical mechanisms of this endocrine disruption are not clear, and a better understanding of these modes of action will inform regulators that develop water quality policies to protect fish populations and aquatic ecosystem health.*******The overall goal of this proposed research is to determine mechanisms of developmental toxicity and metabolic disruption arising from Se exposure in fishes. We will use an integrative approach, combining molecular, biochemical, pharmacological, and behavioural techniques to achieve this goal. To test the hypothesis that early life stage developmental toxicities caused by Se arise from oxidative stress (Objective 1), we will use zebrafish embryos exposed to Se in the presence and absence of inducers and inhibitors of antioxidant defenses, followed by determination of gene expression, oxidative stress markers, and deformities in hatched fry. To test the hypothesis that dietary Se exposure in fishes causes an adverse metabolic syndrome that resembles Type II diabetes in humans (Objective 2), we will use zebrafish and rainbow trout to determine effects on key intermediary metabolic processes that regulate energy homeostasis and aerobic metabolism. To test the hypothesis that Se exposure causes impairment of the visual system in fishes (Objective 3), we will use zebrafish to determine expression of key genes involved in eye development, histopathology of eye structures, and functional responses via several behavioural assays that provide evidence of a fully functional visual system.*******Overall, these innovative, integrated experiments will increase our mechanistic understanding of the toxicological responses associated with environmentally relevant Se exposures, which may be applicable to other classes of aquatic contaminants that display a common etiology. The objectives of this research proposal fit closely with my long-term research goal, which is to investigate mechanisms of developmental and reproductive toxicities in fishes exposed to priority aquatic pollutants.******