Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on toxicologically relevant gene expression profiles in a liver-on-a-chip model

Megan E Solan; Bennett Schackmuth; Erica D Bruce; Sahar Pradhan; Christie M Sayes; Ramon Lavado

doi:10.1016/j.envpol.2023.122610

Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on toxicologically relevant gene expression profiles in a liver-on-a-chip model

Environ Pollut. 2023 Nov 15:337:122610. doi: 10.1016/j.envpol.2023.122610. Epub 2023 Sep 22.

Authors

Megan E Solan¹, Bennett Schackmuth¹, Erica D Bruce¹, Sahar Pradhan¹, Christie M Sayes¹, Ramon Lavado²

Affiliations

¹ Department of Environmental Science, Baylor University, Waco, TX, 76798, USA.
² Department of Environmental Science, Baylor University, Waco, TX, 76798, USA. Electronic address: Ramon_Lavado@baylor.edu.

PMID: 37742859
DOI: 10.1016/j.envpol.2023.122610

Abstract

Short-chain per- and polyfluoroalkyl substances (PFAS) are highly stable and widely used environmental contaminants that pose potential health risks to humans. Aggregating reliable mechanistic information for safety assessments necessitates physiologically relevant high-throughput screening approaches. Here, we demonstrated the utility of a liver-on-a-chip model to investigate the effects of five short-chain PFAS at low (1 nM) and high (1 μM) concentrations on toxicologically-relevant gene expression profiles using the QuantiGene® Plex Assay. We found that the short-chain PFAS tested in this study modulated the expression of ABCG2, a gene encoding for the breast cancer resistance protein (BCRP), with marked and significant upregulation (up to 4-fold) observed for all but one of the short-chain PFAS tested. PFBS and HFPO-DA repressed SLCO1B3 expression, a gene that encodes for an essential liver-specific organic anion transporter. High concentrations of PFBS, PFHxA, and PFHxS upregulated the expression of genes encCYP1A1,CYP2B6 and CYP2C19 with the same treatments resulting in the repression of the expression of the gene encoding CYP1A2. This dysregulation could have consequences for the clearance of endogenous compounds and xenobiotics. However, we acknowledge that increased expression of genes encoding for transporters and biotransformation enzymes may or may not indicate changes to their protein expression or activity. Overall, our study provides important insights into the effects of short-chain PFAS on liver function and their potential implications for human health. The use of the liver-on-a-chip model in combination with the QuantiGene® Plex Assay may be a valuable tool for future high-throughput screening and gene expression profiling in toxicology studies.

Keywords: CYP450; HepaRG; High-throughput screening; Liver-on-a-chip; OrganoPlate; QuantiGene®; Short-chain PFAS.

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2
Alkanesulfonic Acids*
Fluorocarbons* / analysis
Fluorocarbons* / toxicity
Humans
Lab-On-A-Chip Devices
Liver / chemistry
Neoplasm Proteins
Transcriptome
Water Pollutants, Chemical* / analysis

Substances

ATP Binding Cassette Transporter, Subfamily G, Member 2
Water Pollutants, Chemical
Neoplasm Proteins
Fluorocarbons
Alkanesulfonic Acids