Citation:

Addicks, G., A. Rowan-Carroll, A. Reardon, K. Leingartner, A. Williams, M. Meier, I. Moffat, R. Carrier, L. Lorusso, B. Wetmore, C. Yauk, AND E. Atlas. Per- and polyfluoroalkyl substances (PFAS) in mixtures show additive effects on transcriptomic points of departure in human liver spheroids. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 194(1):38-52, (2023). https://doi.org/10.1093/toxsci/kfad044

Impact/Purpose:

PFAS represent a wide range of chemicals used in a variety of consumer and industrial products which results in simultaneous exposures to mixtures of PFAS. This study leverages analyses of transcriptomic changes following exposure in an in vitro liver model to PFAS alone or in 8 mixture combinations.  In vitro points of departure across these exposure scenarios are compared to determine whether PFAS co-exposures will alter potencies in an additive, synergistic and/or antagonistic manner.  For most of the tested mixtures, potencies followed a concentration addition response pattern. These findings are important in furthering understanding of how PFAS co-exposure may impact in vitro potencies.

Description:

Per- and polyfluoroalkyl substances (PFAS) are a wide range of chemicals that are used in a variety of consumer and industrial products leading to direct human exposure. Many PFAS are chemically nonreactive and persistent in the environment, resulting in additional exposure from water, soil, and dietary intake. While some PFAS have documented negative health effects, data on simultaneous exposures to multiple PFAS (PFAS mixtures) are inadequate for making informed decisions for risk assessment. The current study leverages data from previous work in our group using Templated Oligo-Sequencing (TempO-Seq) for high-throughput transcriptomic analysis of PFAS-exposed primary human liver cell spheroids; herein, we determine the transcriptomic potency of PFAS in mixtures. Gene expression data from single PFAS and mixture exposures of liver cell spheroids were subject to benchmark concentration (BMC) analysis. We used the 25th lowest gene BMC as the point of departure to compare the potencies of single PFAS to PFAS mixtures of varying complexity and composition. Specifically, the empirical potency of 8 PFAS mixtures were compared to predicted mixture potencies calculated using the principal of concentration addition (ie, dose addition) in which mixture component potencies are summed by proportion to predict mixture potency. In this study, for most mixtures, empirical mixture potencies were comparable to potencies calculated through concentration addition. This work supports that the effects of PFAS mixtures on gene expression largely follow the concentration addition predicted response and suggests that effects of these individual PFAS in mixtures are not strongly synergistic or antagonistic.

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