Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism

Purpose: The goal of this study was to investigate how PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner Methods: HepaRG cells, which are human-derived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Results: Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. Conclusion: There is strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner The fully differentiated HepaRG cells were then treated with vehicle control (0.1% DMSO), CITCO (1 µM, Sigma-Aldrich), RIF (10 µM, Sigma-Aldrich), BDE-47 (25 µM, Chem Service Inc., West Chester, PA, Catalog No.), or BDE-99 (25 µM, AccuStandard Inc., New Haven, CT, Catalog No.) in triplicates for 24 hours