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

暴露于硒的鱼类的发育毒性和代谢破坏机制

• 批准号: RGPIN-2016-05131
• 负责人: Janz, David
• 金额: $ 3.72万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615518
• 关键词: Mechanisms; developmental; toxicity; metabolic; disruption

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.

硒(Se)是一种必需的微量元素，在必需剂量和毒性剂量之间存在很小的差距，特别是在鱼类中。加拿大和全球的各种工业、农业和市政做法导致淡水生态系统中的硒负荷增加。因此，包括加拿大在内的许多国家目前正在修订其对Se的监管政策，以确保对鱼类种群的保护。 众所周知，硒是一种有效的发育毒物，可导致暴露于高硒饲料中的成年雌性鱼类的眼睛、颅骨、脊柱和其他解剖结构严重畸形。我们课题组最近的工作也表明，高硒暴露会破坏鱼类的几个内分泌系统，这些内分泌系统涉及能量平衡、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，更好地了解这些行动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机构提供信息。 这项拟议研究的总体目标是确定硒暴露对鱼类的发育毒性和代谢干扰的机制。我们将使用一种综合的方法，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发育毒性是由氧化应激引起的假设(目标1)，我们将使用斑马鱼胚胎在存在和不存在抗氧化防御诱导剂和抑制剂的情况下暴露于Se，然后测定孵化出的鱼苗的基因表达、氧化应激标志物和畸形。为了验证这样一种假设，即鱼类饮食中的硒暴露会导致类似于人类II型糖尿病的不良代谢综合征(目标2)，我们将使用斑马鱼和彩虹鲑鱼来确定对调节能量动态平衡和有氧代谢的关键中间代谢过程的影响。为了验证Se暴露导致鱼类视觉系统损伤的假设(目标3)，我们将使用斑马鱼来确定与眼睛发育、眼睛结构的组织病理学和功能反应有关的关键基因的表达，通过几种行为分析提供证据，证明视觉系统完全正常。 总体而言，这些创新的综合实验将增加我们对与环境相关的Se暴露相关的毒理学反应的机械性理解，这可能适用于显示共同病因学的其他类别的水污染物。这项研究方案的目标与我的长期研究目标非常吻合，即研究优先水生污染物对鱼类发育和生殖毒性的机制。