Population-specific transcriptomic bioactivity assessment of perfluorooctanoic acid using human liver spheroids and physiologically based toxicokinetic modeling.

Dunja Kokai, Katarina Borkovic, Marija Kostic, Nemanja Todorovic, Mladena Lalic-Popovic, Bojana Stanic, Nebojsa Andric

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Article in Archives of toxicology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

7 authors.

Dunja KokaiFaculty of Sciences, Department of Biology and Ecology, University of Novi Sad, Trg Dositeja Obradovica 2, Novi Sad, 21000, Serbia.

Katarina BorkovicFaculty of Sciences, Department of Biology and Ecology, University of Novi Sad, Trg Dositeja Obradovica 2, Novi Sad, 21000, Serbia.

Marija KosticFaculty of Sciences, Department of Biology and Ecology, University of Novi Sad, Trg Dositeja Obradovica 2, Novi Sad, 21000, Serbia.

Nemanja TodorovicFaculty of Medicine, Department of Pharmacy, University of Novi Sad, Novi Sad, Serbia.

Mladena Lalic-PopovicFaculty of Medicine, Department of Pharmacy, University of Novi Sad, Novi Sad, Serbia.

Bojana StanicFaculty of Sciences, Department of Biology and Ecology, University of Novi Sad, Trg Dositeja Obradovica 2, Novi Sad, 21000, Serbia. bojana.stanic@dbe.uns.ac.rs.ORCID http://orcid.org/0000-0002-3049-4190

Nebojsa AndricFaculty of Sciences, Department of Biology and Ecology, University of Novi Sad, Trg Dositeja Obradovica 2, Novi Sad, 21000, Serbia.

Funding

Science Fund of the Republic of Serbia 7010

6 · The paper itself

Abstract

Perfluorooctanoic acid (PFOA) has been widely used in industrial and consumer products and was recently classified as a Group 1 carcinogen by the International Agency for Research on Cancer. However, uncertainties remain regarding transcriptomic bioactivity thresholds associated with liver effects and their variability across clinically relevant populations. In this study, previously published transcriptomic data obtained following 24-h and 10-day exposure of primary human liver spheroids (LS) to PFOA were integrated into a physiologically based toxicokinetic (PBTK), population-specific framework to estimate transcriptomic human equivalent doses (HEDs). In addition, exploratory concordance analysis was performed between PFOA-responsive genes and liver hepatocellular carcinoma (LIHC)-associated transcriptomic profiles. Median transcriptomic HEDs ranged from 283 to 412 µg/kg body weight (bw)/week and were substantially higher than the estimated HEDs corresponding to the 95th percentile serum PFOA concentration in the U.S. population (0.0099 µg/kg bw/week) and the mean PFOA concentrations reported in human liver tissue samples (0.035 µg/kg bw/week). Obesity class III, cirrhosis Child-Pugh classes A and B, and non-alcoholic fatty liver disease reduced transcriptomic HEDs by approximately 31-41% compared with the healthy population, although HEDs remained substantially above reference values. Gene-level analysis identified only a limited number of genes within the bioactivity exposure ratio range of 1-100. More than 50% of PFOA-responsive genes exhibited concordant expression patterns with LIHC-associated transcriptomic profiles. Although the biological significance of these overlaps remains uncertain, concordance significantly exceeded that expected by chance from a background gene set and was driven mainly by down-regulated genes. Overall, this study provides a population-informed framework for integrating transcriptomic bioactivity data with PBTK modeling in human-relevant assessment of PFOA-associated liver effects.

Indexed as

Human equivalent doseLiver spheroidsPBTK modelingPerfluorooctanoic acidPopulation variabilityTranscriptomics

Identifiers

PMID42919935

DOI10.1038/s41388-026-03769-x

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