Replacement per- and polyfluoroalkyl substances (PFAS) are potent modulators of lipogenic and drug metabolizing gene expression signatures in primary human hepatocytes

Authors

Emily Marques, University of Rhode Island
Marisa Pfohl, University of Rhode Island
Wei Wei, University of Rhode Island
Giuseppe Tarantola, University of Rhode Island
Lucie Ford, Salve Regina University
Ogochukwu Amaeze, University of Lagos
Jessica Alesio, University of Rhode Island
Sangwoo Ryu, University of Rhode Island
Xuelian Jia, Center for Computational and Integrative Biology
Hao Zhu, Center for Computational and Integrative Biology
Geoffrey D. Bothun, University of Rhode Island
Angela Slitt, University of Rhode Island

Document Type

Article

Date of Original Version

5-1-2022

Abstract

Per- and polyfluoroalkyl substances (PFAS) are a class of environmental toxicants, and some, such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), have been associated with hepatic steatosis in rodents and monkeys. It was hypothesized that perfluorosulfonic acids (C4, 6, 8), perfluorocarboxylic acids (C4–14), perfluoro(2-methyl-3-oxahexanoic) acid (HFPO-DA), 1H, 1H, 2H, 2H-perfluorooctanesulfonic acid (6:2 FTS) along with 3 PFOS precursors could induce expression of lipid metabolism genes and lipid deposition in human hepatocytes. Five-donor pooled cryopreserved human hepatocytes were cultured and treated with 0.1% DMSO vehicle or various PFAS (0.25 to 25 μM) in media. After a 48-h treatment, mRNA transcripts related to lipid transport, metabolism, and synthesis were measured using a Quantigene Plex assay. After 72-h treatments, hepatocytes were stained with Nile Red dye to quantify intracellular lipids. Overall, PFAS were transcriptionally active at 25 μM. In this model, lipid accumulation was not observed with C8-C12 treatments. Shorter chain PFAS (C4-C5), 6:2 FTS, and PFOS precursor, metFOSA, induced significant liver lipid accumulation, and gene activation at lower concentrations than legacy PFAS. In summary short chain PFAS and other alternative PFAS were more potent gene inducers, and potential health effects of replacement PFAS should be critically evaluated in humans.

Publication Title, e.g., Journal

Toxicology and Applied Pharmacology

Volume

442

Citation/Publisher Attribution

Marques, Emily, Marisa Pfohl, Wei Wei, Giuseppe Tarantola, Lucie Ford, Ogochukwu Amaeze, Jessica Alesio, Sangwoo Ryu, Xuelian Jia, Hao Zhu, Geoffrey D. Bothun, and Angela Slitt. "Replacement per- and polyfluoroalkyl substances (PFAS) are potent modulators of lipogenic and drug metabolizing gene expression signatures in primary human hepatocytes." Toxicology and Applied Pharmacology 442, (2022). doi: 10.1016/j.taap.2022.115991.