Simply forever: Tackling PFAS complexity through mode of action assignment

全氟烷基和多氟烷基物质（PFAS）是全球关注的一组异质污染物。目前，对特定PFAS构成的风险，特别是在陆地环境中的风险知之甚少。结构、化学性质和毒理学效应之间的弱相关性（这可能会限制交叉阅读和QSAR的使用）意味着需要新的方法来识别更危险的PFAS，并进一步支持暴露和危害评估的分组。与潜在的靶位点（例如，过氧化物酶体增殖物激活受体和其他受体）相互作用，以及这种相互作用如何破坏基因表达网络和代谢系统。这种综合分析将使我们能够开发新的生理模型的毒性，可用于分类PFAS的吸收模式和作用机制，在不同的陆地物种代表的主要分支的生命之树。在基因和代谢物水平上将暴露和摄取与机制毒理学联系起来的雄心勃勃的目标现在在拟议的规模上是容易处理的，这是由于最近基因组可用性的爆炸，转录组学和代谢组学通量的增加以及生物统计学的进步。暴露对3种分类学上不同的陆生物种的细胞和顶端影响。

Per- and poly-fluoroalkyl substances (PFAS) are a heterogenous group of contaminants of global concern. Currently, the risks posed by specific PFAS, especially in terrestrial environments, are poorly understood. Weak correlations between structure, chemical properties and toxicological effects (which may limit read-across and the use of QSARs) means new approaches are needed that can identify the more hazardous PFAS and further can support grouping for exposure and hazard assessment.Working with 3 phylogenetically distant terrestrial taxa, we will study how 16 carefully selected PFAS from four classes bioaccumulate; interact with potential target sites (e.g. PPAR and other receptors), and how such interactions disrupt gene expression networks and metabolic systems. This integrated analysis will allow us to develop new physiological models of toxicity that can be used to classify PFAS by uptake patterns and mechanisms of action in different terrestrial species representing major branches of the tree of life. The ambitious objective of linking exposure and uptake with mechanistic toxicology at the gene and metabolite level is now tractable at the proposed scale due to the recent explosion of genome availability, increased transcriptomic and metabolomic throughput and advances in biostatistics.In this project we will develop a mechanism of action based compound grouping for PFAS by integrating the transcriptomic, metabolic, cellular and apical effects of exposure on 3 taxonomically diverse terrestrial species.