Simply forever: Tackling PFAS complexity through mode of action assignment

全氟烷基物质和多氟烷基物质(PFAS)是全球关注的一组非均质污染物。目前，人们对特定全氟辛烷磺酸带来的风险知之甚少，特别是在陆地环境中。结构、化学性质和毒理学效应之间的弱相关性(这可能限制阅读和QSARs的使用)意味着需要新的方法来识别更危险的PFAs，并进一步支持分组暴露和危害评估。我们将与3个系统发育上相距遥远的陆地类群合作，研究从四个类别中精心挑选的16个PFAs如何生物积累；与潜在的靶点(例如PPAR和其他受体)相互作用，以及这些相互作用如何扰乱基因表达网络和代谢系统。这一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树主要分支的不同陆地物种的吸收模式和作用机制对全氟辛烷磺酸进行分类。由于最近基因组可获得性的爆炸性增长、转录和代谢组吞吐量的增加以及生物统计学的进步，在基因和代谢物水平上将暴露和吸收与机制毒理学联系起来的雄心勃勃的目标现在是容易处理的。在这个项目中，我们将通过整合暴露在3个分类上不同的陆地物种上的转录、代谢、细胞和顶端效应来开发一种基于作用的化合物分组机制用于PFAS。

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.