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Unraveling Human Hepatocellular Responses to PFAS and Aqueous Film-Forming Foams (AFFFs) for Molecular Hazard Prioritization and In Vivo Translation

Kevin A. Mauge-Lewis1,‡, Sreenivasa C. Ramaiahgari1,‡, Scott S. Auerbach1, Georgia K. Roberts1, Suramya Waidyanatha1, Suzanne E Fenton1, Dhiral P. Phadke2, Michele R. Balik-Meisner2, Arpit Tandon2, Deepak Mav2, Brian Howard2, Ruchir Shah2, Barney Sparrow3, Jenni Gorospe3, Stephen S. Ferguson1

‡These authors equally contributed to this study.
1Division of Translational Toxicology at the National Institute for Environmental Sciences, Research Triangle Park, North Carolina
2Sciome, Research Triangle Park, North Carolina
3Battelle, Columbus, Ohio

DOI: https://doi.org/10.22427/NTP-DATA-500-017-001-000-4

Publication

Abstract

Aqueous film-forming foams (AFFFs) are complex product mixtures that often contain per-and poly- fluorinated alkyl substances (PFAS) to enhance fire suppression and protect firefighters. However, PFAS have been associated with a range of adverse health effects (e.g., liver and thyroid disease, cancer), and innovative approach methods to better understand their toxicity potential and identify safer alternatives are needed. In this study, we investigated a set of 30 substances (e.g., AFFF, PFAS, and clinical drugs) using differentiated cultures of human hepatocytes (HepaRG™, 2D), high throughput transcriptomics, deep learning of cell morphology images, liver enzyme leakage assays, and benchmark dose analysis that: 1) predict the potency ranges for human liver injury, 2) delineate gene- and pathway-level transcriptomic points-of-departure for molecular hazard characterization and prioritization, 3) characterize human hepatocellular response similarities to inform regulatory read-across efforts, and 4) introduce an innovative approach to translate mechanistic hepatocellular response data to predict PFAS-induced hepatomegaly potency. Collectively, these data fill important mechanistic knowledge gaps with PFAS/AFFF and represent a scalable platform to address the thousands of PFAS in commerce for greener chemistries and next generation risk assessments.

Data

Figures

Transcriptomic Analysis Files

Transcriptomic Data Files

LDH Leakage

Images With Deep Learning Calls on Morphology With EC10 Values

ATP Depletion Data via CellTiter-Glo

References to NTP Toxicity Reports: