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Transcriptomic analysis of HepG2 cells treated with BDE-47, BDE-99, BDE-209 and their ternary mixture at 1nM as a dietary relevant concentration

ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are persistent organic chemicals implied as flame re-tardants. Humans are mainly exposed to BDE-47, -99 and -209 congeners by diet. PBDEs are metabolic disruptors with liver as main target organ. To investigate their mode of action at a human relevant concentration, we exposed HepG2 cells to these congeners and their mixture at 1 nM for 72h, analyzing their transcriptomic and proteomic profiles. KEGG pathways and GSEA Hallmarks enrichment analyses evidenced that BDE-47 disrupted the glucose metabolism and Hypoxia pathway; all the congeners and the MIX affected lipid metabolism and signaling Hallmarks regulating metabolism as mTORC1 and PI3K/AKT/MTOR. These results were confirmed by glucose secretion depletion and increased lipid accumulation, especially in BDE-47 and -209 treated cells. These congeners also affected the EGFR/MAPK signaling; further, BDE-47 enriched the Estrogen pathway. Interestingly, BDE-209 and the MIX increased ERα gene expression, whereas all the congeners and the MIX induced ERβ and PPARγ. We also found that PBDEs modulated several lncRNAs and that HNRNAP1 represented a central hub in all the four interaction networks. Overall, despite the low concentration used, the PBDEs investigated affected glucose and lipid metabolism with different underlying modes of action, as highlighted by the integrated omics analysis. These results may support the mechanism-based risk assessment of these compounds in relation to liver metabolism disruption.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216590 | GEO | 2022/10/28

REPOSITORIES: GEO

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Project description:Polychlorinated diphenyl ethers are lipophilic, persistent, and bioaccumulable compounds widely used as flame-retardants. These are chemicals of increasing environmental concern due to their lipophilic, persistent, and bioaccumulable characteristics. The objective of this study was to analyze the potential bioavailability and bioaccumulation of BDE-209 as a source of toxicity. Zebrafish embryos were exposed for 8 days to sediments spiked with an environmentally relevant concentration of BDE-209. We analyzed gene expression changes, thyroid function, and several markers for neurotoxicity. Results of this research highlight the need to consider the capability of BDE-209 to be bioavailable and bioaccumulate, indicating the potential hazardous effects. Total RNA was isolated using RNeasy kits (Qiagen, Valencia, CA, USA). The RNA quality was assessed with an Agilent 2100 Bioanalyzer (Agilent, Wilmington, DE, USA) and quantity was determined using a NanodropM-BM-. ND-1000 spectrophotometer. Total RNA was stored at -80oC until analyzed with oligonucleotide microarrays. Zebrafish 44,000 gene arrays (Agilent Single Color 19161, Platform number GPL6457) were purchased from Agilent (Sta. Clara, CA, USA). The Agilent one-color microarray hybridization protocol (One-Color Microarray-Based Gene Expression Analysis, version 5.7, Agilent Technologies, Palo Alto, CA) was used for microarray hybridizations following the manufacturerM-bM-^@M-^Ys protocol and recommendations. Four controls and four treated samples were analyzed, each sample consisting of a pool of embryos. One ug of total RNA was used for all hybridizations. cDNA synthesis, cRNA labeling, amplification and hybridization were performed following the manufacturerM-bM-^@M-^Ys kits and protocols (Quick Amp Labeling kit; Agilent, Palo Alto, CA). An Axon GenePixM-BM-. 4000B Microarray Scanner (Molecular Devices Inc., Sunnyvale, CA) was used to scan microarray images at 5 M-NM-<m resolution. Data were resolved from microarray images using Agilent Feature Extraction software and analyzed using GeneSpring (Agilent Technologies, Palo Alto, CA).

Dataset Information

Transcriptomic analysis of HepG2 cells treated with BDE-47, BDE-99, BDE-209 and their ternary mixture at 1nM as a dietary relevant concentration

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