Critical evaluation of ToxCast-Reactome predicted toxicity pathway correspondence of the human liver HepG2 activity profile with observed PFOA and PFOS hazards

Toxicity by Descent: A Comparative Approach for Chemical Hazard Assessment

“…Pathway-based approaches are gaining acceptance for grouping and prioritizing data-poor chemicals for more detailed toxicity studies, based on profiling genes that are indicative of the chemical mechanisms of action. For example, the knowledge of toxicity mechanisms for hundreds of per-and polyfluoroalkyl substances (PFAS) is growing to include pathways that are inferred using the Reactome database (Houck et al, 2021;Massarsky et al, 2022). Several pathways identified through this ToxCast-Reactome framework are supported by epidemiology or laboratory studies that signal mechanisms contributing to (i) hepatotoxicity via the dysregulation of lipid metabolism by peroxisome proliferator-activated receptor-α (PPAR-α), (ii) immunotoxicity via the Fc epsilon receptor and interleukins (ILs) signalling pathways, and (iii) disease via the PI3K/AKT signalling in cancer and CDK5 triggered neurodegeneration (see references within Massarsky et al, 2022).…”

“…For example, the knowledge of toxicity mechanisms for hundreds of per-and polyfluoroalkyl substances (PFAS) is growing to include pathways that are inferred using the Reactome database (Houck et al, 2021;Massarsky et al, 2022). Several pathways identified through this ToxCast-Reactome framework are supported by epidemiology or laboratory studies that signal mechanisms contributing to (i) hepatotoxicity via the dysregulation of lipid metabolism by peroxisome proliferator-activated receptor-α (PPAR-α), (ii) immunotoxicity via the Fc epsilon receptor and interleukins (ILs) signalling pathways, and (iii) disease via the PI3K/AKT signalling in cancer and CDK5 triggered neurodegeneration (see references within Massarsky et al, 2022). Our method of evaluating the likely conservation of pathwayswith results presented within the supplemental tablesdemonstrates that some, but not all such toxicologically-relevant pathways are expected to be shared between humans and distantly related species when perturbed by PFAS.…”