Determination of lipid dysregulation by per- and polyfluorinated alkyl substances (PFAS) in aquatic macroinvertebrates

全氟和多氟烷基物质（PFAS）包括一系列广泛的化学品，估计包括4，730种独特的化学品，更大的估计将这一数字置于14，735种不同的结构中。全氟和多氟烷基物质（PFAS）包括一系列广泛的化学品，估计包括4，730种独特的化学品，更大的估计将这一数字置于14，735种不同的结构中。这些化学品对环境的广泛污染与人类的多种影响有关，如癌症、甲状腺疾病、肝损伤和生育能力下降。最近的研究还表明，对动物健康的不利影响与新陈代谢、免疫功能、内分泌干扰和神经发育有关。虽然已经观察到影响，但缺乏将因果关系联系起来的潜在机制，并且仍然存在关于PFAS暴露的重大知识差距，包括吸收和膜转运行为。PFAS的蓄积有可能破坏脂质代谢，有证据表明脂解功能障碍、β-氧化以及对葡萄糖代谢的进一步影响。代谢是正常生理功能和稳态控制的关键部分，通过分析代谢组，它可以提供一个分子指纹，该指纹是表型锚定的，以揭示因果关系背后的机制。此外，PFAS的混合物组合物可引发不同类型的毒性，这使基于效应的研究进一步复杂化，并将需要新的深入分子方法来描述毒理学结果。本项目的目的是使用脂质组学确定PFAS化学品在淡水大型无脊椎动物中的暴露，以避免代谢功能障碍。这一目标将通过使用靶向和非靶向质谱法监测英国环境中存在的PFAS化学品来实现。然后将生物体在受控实验室条件下暴露于单一和几种相关PFAS化学品的组合，以确定脂质代谢的变化。与PFAS暴露相关的分子途径的确定将发展成因果生物网络，以解决有关毒理学结果的知识空白。

Per- and polyfluorinated alkyl substances (PFAS) encompass a broad suite of chemicals which have been estimated to include 4,730 unique chemicals, with larger estimates placing this number at 14,735 different structures. Per- and polyfluorinated alkyl substances (PFAS) encompass a broad suite of chemicals which have been estimated to include 4,730 unique chemicals, with larger estimates placing this number at 14,735 different structures. The widespread contamination of the environment with these chemicals has been linked to multiple effects in humans such as cancer, thyroid disease, liver damage and decreased fertility. Recent research has also demonstrated adverse effects in animal health associated with metabolism, immune function, endocrine disruption and neurodevelopment. Whilst effects have been observed the underlying mechanisms that link cause to effect are lacking and remains a significant knowledge gap concerning PFAS exposures including the uptake and membrane transport behaviours. The accumulation of PFAS has the potential to disrupt lipid metabolism with evidence suggesting dysfunction in lipolysis, beta-oxidation with further consequences for glucose metabolism. Metabolism is a critical part of normal physiological function and homeostatic control and by analysing the metabolome it can provide a molecular fingerprint that is phenotypically anchored to reveal mechanisms behind cause-effect relationships. Moreover, mixture composition of PFAS can trigger different types of toxicities which further complicates effect-based studies and will require novel in-depth molecular approaches to delineate the toxicological outcomes. The aim of this project will be to determine the exposure of PFAS chemicals in freshwater macroinvertebrates to characterise metabolic dysfunction using lipidomics. The aim will be achieved through surveillance of PFAS chemicals present in the UK environment using targeted and non-target mass spectrometry. Organisms will then be exposed under controlled laboratory conditions to single and combinations of several relevant PFAS chemicals to determine alterations in lipid metabolism. Determination of molecular pathways linked to PFAS exposure will be developed into causal biological networks that will address knowledge gaps concerning toxicological outcomes.