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PROTECT: Predicting teleost fish species' sensitivity at molecular initiating events

保护：预测硬骨鱼类对分子起始事件的敏感性

基本信息

批准号：
NE/X000192/1
负责人：
Nicolas Bury
金额：
$ 36.65万
依托单位：
University of Southampton
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=NE%2FX000192%2F1
关键词：
PROTECT Predicting teleost fish species

项目摘要

We are losing biodiversity at an alarming rate, so much so that we are now in a 6th mass extinction event. The reasons for this are varied and include habitat loss, climate change and chemical pollution. Restoration of habitats has the potential to increase biodiversity, but a positive outcome will be limited if chemical pollution is not tackled and remains at a level that is detrimental to wildlife. To guide policy on where to prioritise resources for beneficial pollution mitigation and habitat restoration strategies, it is necessary to identify those species that are the most sensitive to a pollutant and are under threat of extinction.Chemicals exert their toxicity via interacting with proteins, termed the molecular initiating event. If the organism is unable to respond to this toxic insult, then the individual's health may be impacted, leading to effects at a population level. Understanding the factors that determine how a chemical interacts at the molecular initiating event is a key component for predictive toxicology at the individual species level.Mutations can alter a protein's structure and function. We know that single mutations in human genes can alter protein function and lead to disease. With millions of species, thousands of proteins and thousands of chemicals released into the environment it is not surprising that there is a large range of species sensitivities to pollutants. Species sensitivity distribution curves confirm this and show these large differences can occur between closely related species. Species sensitivity is derived from toxicity tests. There is recognition that it is unethical to continue killing organisms, and there is a push to find alternative strategies such as in vitro methods (data derived without the use of animals) and in-silico approaches (the use of computer programmes) to generate the data necessary to set standards to protect all species, a novel approach called New Approach Methodology.Global initiatives to sequence the genomes of many species has the potential to revolutionise predictive toxicology without further toxicity testing. The genomic resource allows us to identify protein mutations between species. However, not all mutations alter protein function, some are neutral and thus additional functional data is required to identify if changes in proteins involved in the molecular initiating event account for an individual species sensitivity. The aim of the project is to develop a computer-based approach to predict individual species sensitivity by focusing on fish stress receptors, called the corticosteroid receptors which comprise the glucocorticoid and mineralocorticoid receptors. This is because: 1. There are assays available to assess receptor functionality and thus the sensitivity of the molecular initiating event to man-made chemicals.2. There is evidence of differences in the sensitivity of the receptors to steroids in a few species, but not others.3. There is a suite of computer-based tools to identity the key sequence motifs in receptors that confer sensitivity to a chemical.4. Altered corticosteroid receptors' function is detrimental to health and man-made corticosteroids are a growing environmental concern. The project will generate functional information on the interaction of 9 natural and man-made steroids with 53 corticosteroid receptors proteins from 18 fish species representing 14 orders. This information will be used to classify the receptors into those that are hypo or hypersensitive to corticosteroids and interact with another class of steroids progestins. This functional data along with computational analysis will be used to identify common amino acid sequences that classify receptor type. The deliverable of the project will be the ability to identify fish species that are sensitive to man-made corticosteroids, other corticosteroid endocrine disrupting chemicals, progestins and stress based on receptor amino acid sequence alone.

我们正在以惊人的速度失去生物多样性，以至于我们现在正处于第六次大灭绝事件中。造成这种情况的原因多种多样，包括栖息地丧失、气候变化和化学污染。栖息地的恢复有可能增加生物多样性，但如果化学污染不得到解决，并且仍然处于对野生动物有害的水平，那么积极的结果将是有限的。为了指导在何处优先分配资源以实施有益的减轻污染和恢复生境战略的政策，有必要确定那些对污染物最敏感和面临灭绝威胁的物种。化学物质通过与蛋白质的相互作用发挥其毒性，称为分子起始事件。如果生物体不能对这种有毒的侮辱作出反应，那么个人的健康可能会受到影响，导致在种群水平上的影响。了解决定一种化学物质在分子起始事件中如何相互作用的因素，是在单个物种水平上预测毒理学的关键组成部分。突变可以改变蛋白质的结构和功能。我们知道人类基因的单个突变可以改变蛋白质功能并导致疾病。随着数以百万计的物种、成千上万的蛋白质和成千上万的化学物质被释放到环境中，对污染物有很大范围的物种敏感也就不足为奇了。物种敏感性分布曲线证实了这一点，并表明这些巨大的差异可能发生在密切相关的物种之间。物种敏感性是由毒性试验得出的。人们已经认识到继续杀死生物是不道德的，并且正在努力寻找替代策略，例如体外方法（不使用动物的数据）和计算机方法（使用计算机程序）来生成必要的数据，以制定保护所有物种的标准，这是一种被称为新方法方法论的新方法。许多物种基因组测序的全球倡议有可能在无需进一步毒性测试的情况下彻底改变预测毒理学。基因组资源使我们能够识别物种之间的蛋白质突变。然而，并不是所有的突变都改变了蛋白质的功能，有些是中性的，因此需要额外的功能数据来确定参与分子起始事件的蛋白质的变化是否解释了单个物种的敏感性。该项目的目的是开发一种基于计算机的方法，通过关注鱼类的应激受体来预测个体物种的敏感性。应激受体被称为皮质类固醇受体，由糖皮质激素和矿皮质激素受体组成。这是因为：1；有可用的测定方法来评估受体的功能，从而评估分子起始事件对人造化学品的敏感性。有证据表明，在一些物种中，受体对类固醇的敏感性存在差异，而在其他物种中则无差异。有一套基于计算机的工具来识别受体中赋予对化学物质敏感性的关键序列基序。皮质类固醇受体功能的改变对健康是有害的，人造皮质类固醇是一个日益严重的环境问题。该项目将生成9种天然和人造类固醇与来自14目18种鱼类的53种皮质类固醇受体蛋白相互作用的功能信息。这些信息将用于将受体分类为对皮质类固醇低敏感或过敏的受体，并与另一类类固醇黄体酮相互作用。该功能数据以及计算分析将用于识别分类受体类型的常见氨基酸序列。该项目的成果将是能够仅根据受体氨基酸序列确定对人造皮质类固醇、其他皮质类固醇内分泌干扰化学物质、黄体酮和应激敏感的鱼类。