Simply forever: Tackling PFAS complexity through mode of action assignment

全氟烷基和多氟烷基物质（PFAS）是一类异质性污染物，受到全球关注。目前，人们对特定PFAS造成的风险，特别是在陆地环境中造成的风险知之甚少。结构、化学性质和毒理学效应之间的弱相关性（这可能限制QSARs的解读和使用）意味着需要新的方法来识别更危险的PFAS，并进一步支持对暴露和危害评估进行分组。在3个系统发育上遥远的陆地分类群中，我们将研究从4类中精心挑选的16种PFAS如何生物积累；与潜在的靶点（如PPAR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毒性生理模型，可用于根据代表生命之树主要分支的不同陆生物种的摄取模式和作用机制对PFAS进行分类。将暴露和摄取与基因和代谢物水平的机械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可处理的，这是由于最近基因组可用性的爆炸式增长，转录组和代谢组通量的增加以及生物统计学的进步。在本项目中，我们将通过整合暴露对3种不同陆地物种的转录组、代谢、细胞和根尖的影响，建立基于作用的PFAS化合物分组机制。

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.