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High-throughput transcriptomic evaluation of per- and polyfluoroalkyl substances (PFAS) in primary human liver spheroids to inform read-across

By Andrea Rowan-Carroll, Anthony Readon, Karen Leingartner, Remi Gagne, Andrew Williams, Matthew J Meier, Byron Kuo, Julie Bourdon-lacombe, Ivy Moffat, Richard Carrier, Andy Nong, luigi lorusso, Stephen S. Ferguson, Ella Atlas, Carole Yauk

Posted 15 Oct 2020
bioRxiv DOI: 10.1101/2020.10.15.341362

Per- and poly-fluoroalkyl substances (PFAS) are widely found in the environment because of their extensive use and persistence. Although a few PFAS are well studied, most lack toxicity data to inform human health hazard and risk assessment. This study focussed on four model PFAS: perfluorooctanoic acid (PFOA; 8 carbon), perfluorobutane sulfonate (PFBS; 4 carbon), perfluorooctane sulfonate (PFOS; 8 carbon), and perfluorodecane sulfonate (PFDS; 10 carbon). Human primary liver cell spheroids (i.e., pooled-donor) were exposed to 10 concentrations of PFAS over four time-points. The approach aimed to: (1) identify the extent to which the PFAS modulated gene expression; (2) identify similarities in biological responses; (3) compare PFAS potency through benchmark concentration (BMC) analysis; and (4) derive bioactivity exposure ratios (BERs: ratio of concentration at which biological response occurs converted to administered equivalent dose relative to human daily exposure). All PFAS induced transcriptional changes of cholesterol biosynthesis and lipid metabolism, and appeared to activate PPAR. PFOS exhibited the most transcriptional perturbations and had a highly similar gene expression profile to PFDS. PFBS induced the least transcriptional changes and had the highest BMCs. The data indicate that these four chemicals may have common molecular targets and toxicities, but that PFOS and PFDS are the most similar. BERs derived for PFOA and PFOS had relatively low margins; the transcriptomic BER was slightly more conservative than BERs derived from rodent apical endpoints used as points of departure in risk assessment. The data provide a baseline on which to compare the toxicity of other PFAS using this testing strategy.

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