Transcriptional effects of binary combinations of PFAS in FaO cells

Jim Bjork, Douglas A. Dawson, Jacob O. Krogstad, Kendall B. Wallace

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Per- and polyfluoroalkyl substances (PFAS) represent a large class of structurally diverse chemicals of increasing public concern, mostly due to their chemical stability and undetermined toxicity profiles. In laboratory animals, adverse effects implicated for certain PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) in particular, include liver toxicity and the associated metabolic dysregulation, immune and thyroid alterations, reproductive toxicity, and selected tumors. The broad commercialization and environmental distribution of PFAS has drawn attention to the need for understanding risks associated with combined exposure to multiple PFAS in complex mixtures. The purpose of this investigation is to determine whether binary combinations of PFAS elicit a molecular response that is either greater than or less than the sum of the individual responses. Exposure of FaO rat hepatoma cells for 24 h to 25 μM–200 μM of the 4- and 8-carbon perfluorocarboxylic acids (PFBA and PFOA) or the 4, 6, and 8-carbon perfluorosulfonic acids (PFBS, PFHxS, and PFOS, respectively) individually caused a dose-dependent increase in PPARα-regulated expression of peroxisomal bifunctional enzyme (Ehhadh). Potency increased with carbon number, with the carboxylates eliciting a greater transcriptional response than the corresponding sulfonates. Combined exposure to PFOA and PFBA produced an effect that was significantly less than the sum of the individual responses. The response to the combination of PFOA and PFOS produced a summative effect at concentrations that were not cytotoxic. Combined exposures to PFOS and either PFBS or PFHxS at low noncytotoxic concentrations produced a transcriptional effect that was significantly less than the sum of the individual effects. The results demonstrate that among the five structurally related perfluoroalkyl acids included in this investigation, PPARα transcriptional activation in response to combined binary exposures is consistently at or below that predicted by the sum of the individual effects.

Original languageEnglish (US)
Article number152997
StatePublished - Dec 2021

Bibliographical note

Funding Information:
This work was supported in-part by an unrestricted research grant from the 3M Co. The authors express no other potentially conflicting interests.

Publisher Copyright:
© 2021 Elsevier B.V.


  • Gene expression
  • Mixtures
  • Nuclear receptors
  • Perfluoroalkyl acids

PubMed: MeSH publication types

  • Comparative Study
  • Journal Article
  • Research Support, Non-U.S. Gov't


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