Chronic exposure to tetrabromodiphenyl ether (BDE-47) aggravates hepatic steatosis and liver fibrosis in diet-induced obese mice

Yang, Chunxue; Zhu, Lin; Kang, Qianjin; Lee, Hin Kiu; Li, Dapeng; Cai, Zongwei

doi:10.1016/j.jhazmat.2019.120766

Cited by 43 publications

(20 citation statements)

References 57 publications

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“…In mice fed a high-fat diet, however, BDE-47 caused an increase of body weight and inflammation through the increased synthesis of triglycerides. In addition to obesity, exposure to BDE-47 may lead to detrimental hepatotoxicity through hepatic steatosis and liver fibrosis [81].…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Kelly

et al. 2020

PLoS ONE

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Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are humanderived 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. 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 alpharetinoid 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. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner.

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Section: Discussionmentioning

confidence: 99%

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

Zhang

Kelly

et al. 2020

PLoS ONE

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“…The sEV samples were diluted in particle-free water (Water, HPLC grade, Sigma-Aldrich, filtered by 20 nm using Whatman Anotop filters) to generate a dilution in which 20-120 particles per frame were tracked, to obtain a concentration within the recommended measurement range (1-10x10 8 particles/mL). Five experiment videos of 60 second duration were analyzed using NTA 3.4 Build 3.4.003 (camera level [15][16]. A total of 1500 frames were examined per sample, which were captured and analyzed by applying instrument-optimized settings with a suitable detection threshold so that the observed particles were marked with red crosses and no more than 5 blue crosses were visible.…”

Section: Nanoparticle Tracking Analysis (Nta) Of Thp-1 Derived Sevsmentioning

confidence: 99%

“…PBDEs have been investigated for their toxicity in both in vitro and in vivo experimental set-ups. A large set of studies has reported that PBDEs might have multi system/organ toxicities in reproductive (11), endocrinological (12), immunological (13), pulmonary (14) and hepatic systems (15). In addition, as reviewed by Cai and coworkers (4), epidemiological studies have suggested an association between human exposure to PBDEs and changes in thyroid hormone regulation and neuropsychological functioning (16).…”

Section: Introductionmentioning

confidence: 99%

2,2’4,4’-Tetrabromodiphenyl Ether (PBDE-47) Modulates the Intracellular miRNA Profile, sEV Biogenesis and Their miRNA Cargo Exacerbating the LPS-Induced Pro-Inflammatory Response in THP-1 Macrophages

Longo

Adamo

et al. 2021

Front. Immunol.

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The 2,2’4,4’-tetrabromodiphenyl ether (PBDE-47) is one of the most prominent PBDE congeners detected in the environment and in animal and human tissues. Animal model experiments suggested the occurrence of PBDE-induced immunotoxicity leading to different outcomes and recently we demonstrated that this substance can impair macrophage and basophil activities. In this manuscript, we decided to further examine the effects induced by PBDE-47 treatment on innate immune response by looking at the intracellular expression profile of miRNAs as well as the biogenesis, cargo content and activity of human M(LPS) macrophage cell-derived small extracellular vesicles (sEVs). Microarray and in silico analysis demonstrated that PBDE-47 can induce some epigenetic effects in M(LPS) THP-1 cells modulating the expression of a set of intracellular miRNAs involved in biological pathways regulating the expression of estrogen-mediated signaling and immune responses with particular reference to M1/M2 differentiation. In addition to the cell-intrinsic modulation of intracellular miRNAs, we demonstrated that PBDE-47 could also interfere with the biogenesis of sEVs increasing their number and selecting a de novo population of sEVs. Moreover, PBDE-47 induced the overload of specific immune related miRNAs in PBDE-47 derived sEVs. Finally, culture experiments with naïve M(LPS) macrophages demonstrated that purified PBDE-47 derived sEVs can modulate macrophage immune response exacerbating the LPS-induced pro-inflammatory response inducing the overexpression of the IL-6 and the MMP9 genes. Data from this study demonstrated that PBDE-47 can perturb the innate immune response at different levels modulating the intracellular expression of miRNAs but also interfering with the biogenesis, cargo content and functional activity of M(LPS) macrophage cell-derived sEVs.

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“…Moreover, in the muscle, Igf1 inhibition has been shown to increase lysosomal proteolysis in this tissue [60, 61], which, together with our observation of decreased expression of this gene across the murine lifespan, may indicate that lysosomal proteolysis is heightened with age in mice. As for Ctsh , despite not being largely studied in the skeletal muscle, its age-associated downregulation reported by us may indicate that cathepsin H-mediated protein degradation also declines with age, as this gene encodes for a lysosomal cysteine protease recently implicated in mediating degradation leading to liver fibrosis [62]. Moreover, DAP1, the protein encoded by the human orthology of Dap , was found to negatively regulate autophagy [63], while lower expression of Dap has also been linked with alterations in regulation of apoptosis and autophagy, resulting in poor clinical outcomes in human cancers [64, 65].…”

Section: Discussionmentioning

confidence: 99%

Integration of differential gene expression with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues

Ferreira

Francisco

Soares

et al. 2021

Preprint

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Gene expression alterations occur in all mouse tissues during aging, but recent works highlight minor rather than major dysregulation amplitude for most genes, questioning whether differentially expressed genes on their own provide deep insight into aging biology. To clarify this issue, we have combined differential gene expression with weighted gene correlation network analysis (WGCNA) to identify expression signatures accounting for the pairwise relations between gene expression profiles and the cumulative effect of genes with small fold-changes during aging in the brain, heart, liver, skeletal muscle, and pancreas of C57BL/6 mice. Functional enrichment analysis of the overlap of genes identified in both approaches showed that immunity-related responses, mitochondrial energy metabolism, tissue regeneration and detoxification are prominently altered in the brain, heart, muscle, and liver, respectively, reflecting an age-related global loss of tissue function. While data showed little overlap among the age-dysregulated genes between tissues, aging triggered common biological processes in distinct tissues, particularly proteostasis-related pathways, which we highlight as important features of murine tissue physiological aging.

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Chronic exposure to tetrabromodiphenyl ether (BDE-47) aggravates hepatic steatosis and liver fibrosis in diet-induced obese mice

Cited by 43 publications

References 57 publications

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

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

2,2’4,4’-Tetrabromodiphenyl Ether (PBDE-47) Modulates the Intracellular miRNA Profile, sEV Biogenesis and Their miRNA Cargo Exacerbating the LPS-Induced Pro-Inflammatory Response in THP-1 Macrophages

Integration of differential gene expression with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues

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