Knowledge Transfer -Impacts of inbreeding on the responses to pharmaceuticals and fitness consequences in fish - a molecular approach

环境中的药物可能会对野生动物甚至人类产生广泛的有害影响，这是环境署处理环境污染的首要议程。野生动物数量下降是由于接触药物造成的（例如亚洲秃鹫的双氯芬酸）。此外，与人类有关的一些生殖疾病现在已成为一个重大的健康问题，与野生动物因接触环境化学品（包括药品）而产生的影响相当。英国在水生环境药物领域处于领先地位，申请人为解释某些此类污染物如何干扰鱼类的正常生殖活动做出了贡献。关于近亲繁殖和接触污染物的相互影响的信息极为有限，而且基本上对药物一无所知，这令人惊讶，因为近亲繁殖的动物品种最常用于化学物质（包括药物）的实验室测试。本项目将提供对药物酮康唑（一种合成抗真菌药物，用作农业农药，临床上用于预防和治疗皮肤和真菌感染）作为一组广泛使用的杀菌剂的代表，对鱼类近交系群体暴露的脆弱性或抗性的了解。使用全基因组方法（基因阵列）将使我们能够解剖出与暴露于这种药物的生理应激最密切相关的基因表达网络。该项目的数据将进一步深入了解鱼类易受对人类健康具有重要意义的药物影响的关键决定因素。有关酮康唑在近交系和远交系种群中的比较反应及其对繁殖动态的影响的数据也将为生态和环境风险评估提供重要信息。因此，这一建议将为鱼类化学暴露效应的基因-环境相互作用提供新的信息。该项目还可能提供一套更为翔实的生物（分子）效应工具，以此为基础对酮康唑和其他相关杀菌剂进行环境影响和健康评估。这项工作将提供有关酮康唑对自然环境的健康影响的实质性信息，以便更好地保护我们的水生资源和生物多样性，并将更广泛地为环境影响评估作出贡献，因此将引起政府监管机构、环境保护团体、工业界和广大公众的广泛兴趣。该项目的一个关键要素是加强学术界（埃克塞特大学）和最终用户（阿斯利康）之间的伙伴关系。这种伙伴关系将促进化学危害识别的遗传和基因组方法（并通过NERC资助的科学开发）进入制药工业。它将进一步促进学术界对化学/制药工业实际研究需求的理解。

Pharmaceuticals in the environment potentially have wide reaching deleterious impacts on wildlife and possibly humans, and are at the top of the Environment Agency's agenda for environmental pollution. Population level declines in wildlife have resulted from exposure to pharmaceuticals (e.g. diclofenac in vultures in Asia). Furthermore, some reproductive disorders associated in humans are now a major health issue and parallel those effects seen in wildlife that have been associated with exposure to environmental chemicals, including pharmaceuticals. The UK holds a strong lead in the field of pharmaceuticals in the aquatic environment and the applicants have contributed to the unfolding explanation of how some such contaminants interfere with normal reproductive activity in fish. . Information on interactive effects of inbreeding and pollutant exposure is extremely limited and essentially nothing is known for pharmaceuticals, which is surprising given that inbred strains of animals are used most commonly for laboratory testing of chemicals, including pharmaceuticals. This project will provide an understanding of the vulnerability or resistance of inbred populations of fish for exposure to the pharmaceutical,ketoconazole (a synthetic antifungal drug employed as an agricultural pesticides and clinically to prevent and treat skin and fungal infections), as a representative of a group of widely used group of fungicides. The use of genome-wide approaches (gene arrays) will enable us to dissect out gene expression networks most intimately associated with physiological stress for exposure to this pharmaceutical. The data from the project will further provide insights into the critical determinants of vulnerability of fish to a pharmaceutical of importance to human health. The data on the comparative responses to ketoconazole in inbred and outbred populations and impacts on breeding dynamics will also be highly informative for ecological and environmental risk assessment. This proposal will thus provide new information on gene-environment interactions for chemical exposure effects in fish. The project is also likely to deliver a more informative set of biological (molecular) effects tools upon which to base environmental impact and health assessments for ketoconazole and other allied fungicides. This work will provide substantive information on the health impacts of ketoconazole in the natural environment for the better protection of our aquatic resources and biodiversity and will contribute more widely to environmental impact assessments and will thus be of very wide interest to the government regulatory bodies, environment protection groups, industry and the wider public. A key element of the project is an enhancement in the partnership between academia (University of Exeter) and an end-user (Astrazeneca). This partnership will facilitate the uptake of genetic and genomic methods for chemical hazard identification (and developed through NERC funded science) into the pharmaceutical industry. It will further facilitate an enhanced understanding in academia of the practical research needs of the chemical/pharmaceutical industry.