That which does not kill us makes us stronger: Differential sensitivity to metal exposure during zebrafish embryogenesis and the impact of pre-exposur

这项研究的目的是记录鱼类模型中性分化和发育的表观遗传调控，以及这一过程如何受到环境应激源的干扰。该项目将解决这样的假设，即性腺内发育中的生殖细胞的(表观)基因组环境在这些生殖细胞的性别决定和随后的分化过程中发挥关键作用。我们还假设，一些环境应激源将扰乱这些过程，潜在地导致繁殖的不利结果，在某些情况下，这可能是通过表观遗传机制遗传的。这项工作将侧重于影响全球鱼类种群的两个普遍存在的压力源--缺氧和双酚A。缺氧是全球淡水和海洋生态系统面临的最重要的全球威胁之一，导致大规模死亡。当氧气耗竭较轻时，鱼类性别分化的中断可能会在受影响的生态系统中产生潜在的种群水平后果。双酚A是塑料的一种成分，存在于全球水产系统中，已在90%以上的受试者中检测到双酚A。暴露于双酚A会扰乱生殖，改变表观遗传标记，并与包括心血管疾病在内的一系列疾病有关。这些应激源在全球范围内引起了极大的关注，需要了解它们是如何造成影响的，以及暴露在这些压力下是否会在以后的生活或后代中导致长期的不利影响。要做到这一点，学生将首先以斑马鱼为模型，研究生殖细胞中性分化和发育的表观基因组调控。这将通过在发生主要性别分化事件的发育窗口分离生殖细胞，并对这些分离细胞上的转录组、甲基组和miRNAs进行量化来实现。然后，学生将测试暴露在低氧和双酚A下如何影响生殖细胞的发育。最后，学生将通过进行多代研究，调查这些应激源的不利影响是否可以通过表观遗传机制遗传给后代。拟议工作的研究成果将首次提供调控生殖细胞性分化和发育的表观经济学因素的全球特征，以及全球重要应激源对这些过程的影响。鉴于繁殖对鱼类种群可持续性的重要性，这一知识对于支持适当的管理和监管决策以及更好地保护水生环境具有高度相关性。学生将从学术和政府研究环境的杰出培训、支持和设施中受益，包括学科具体培训和可转移技能的通用培训，并将被培养为能够为国际研究界做出贡献的独立科学家。

This studentship aims to document the epigenetic regulation of sexual differentiation and development in a fish model and how this process is perturbed by exposure to environmental stressors. The project will address the hypothesis that the (epi)genomic environment of the developing germ cells within the gonads plays a key role on the process of sex determination and subsequent differentiation of those germ cells. We also hypothesise that that some environmental stressors will perturb these processes, potentially leading to adverse outcomes for reproduction, which may be inheritable via epigenetic mechanisms in some cases. The work will focus on two ubiquitous stressors affecting fish populations worldwide, hypoxia and bisphenol A. Hypoxia is one of the most important global threats to freshwater and marine ecosystems worldwide, resulting in mass mortalities. When oxygen depletion is mild, disruption of sex differentiation in fish can to occur with potential population level consequences in affected ecosystems. Bisphenol A, a component of plastics, is present in aquatic systems globally and has been detected in over 90% of people tested. Exposure to bisphenol A causes disruption of reproduction, changes in epigenetic markers and is associated with a wide range of diseases including cardiovascular disease. These stressors are of great concern globally and there is a need to understand how they cause their effects and whether exposures can result in long term adverse effects later in life or in subsequent generations.To do this, the student will first investigate the epigenomic regulation of sexual differentiation and development in the germ cells using the zebrafish as a model. This will be achieved by isolating germ cells during the developmental windows where major sex differentiation events occur, and quantifying the transcriptome, methylome and miRNAs on those isolated cells. The student will then test how exposures to hypoxia and bisphenol A affect the development of the germ cells. Finally, the student will investigate whether the adverse effects of these stressors can be inherited via epigenetic mechanisms to subsequent generations, by conducting multigenerational studies.The research outcomes of the proposed work will provide the first global characterisation of the epigenomic factors regulating sex differentiation and development in germ cells, and the effects of globally important stressors on those processes. Given the importance of reproduction for the sustainability of fish populations, this knowledge is highly relevant to support appropriate management and regulatory decisions, and to better protect the aquatic environment.The collaboration between Cefas and the University of Exeter will bring together expertise in fish reproductive biology, epigenetics and bioinformatics that will strongly benefit all partners involved. The student will benefit from outstanding training, support and facilities on both academic and governmental research environments, covering both subject specific training and generic training in transferable skills, and will be nurtured to develop as an independent scientist able to contribute to the international research community.