Assessment of fibrotic pathways induced by environmental chemicals using 3D-human liver microtissue model

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Publication date
30.12.2020
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01A - Journal article
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Parent work
Environmental Research
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DOI of the original publication
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Volume
194
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Elsevier
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Abstract
Exposure to environmental chemicals, particularly those with persistent and bioaccumulative properties have been linked to liver diseases. Induction of fibrotic pathways is considered as a pre-requirement of chemical induced liver fibrosis. Here, we applied 3D in vitro human liver microtissues (MTs) composed of HepaRG, THP-1 and hTERT-HSC that express relevant hepatic pathways (bile acid, sterol, and xenobiotic metabolism) and can recapitulate key events of liver fibrosis (e.g. extracellular matrix-deposition). The liver MTs were exposed to a known profibrotic chemical, thioacetamide (TAA) and three representative environmental chemicals (TCDD, benzo [a] pyrene (BaP) and PCB126). Both TAA and BaP triggered fibrotic pathway related events such as he-patocellular damage (cytotoxicity and decreased albumin release), hepatic stellate cell activation (transcriptional upregulation of α-SMA and Col1α1) and extracellular matrix remodelling. TCDD or PCB126 at measured con-centrations did not elicit these responses in the 3D liver MTs system, though they caused cytotoxicity in HepaRG monoculture at high concentrations. Reduced human transcriptome (RHT) analysis captured molecular re-sponses involved in liver fibrosis when MTs were treated with TAA and BaP. The results suggest that 3D, multicellular, human liver microtissues represent an alternative, human-relevant, in vitro liver model for assessing fibrotic pathways induced by environmental chemicals.
Keywords
Liver microtissues, Fibrotic potential assessment, Environmental chemicals
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1096-0953
0013-9351
Language
English
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Yes
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Publication status
Published
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Citation
LU, Yan, Catherine MESSNER und Laura SUTER-DICK, 2020. Assessment of fibrotic pathways induced by environmental chemicals using 3D-human liver microtissue model. Environmental Research. 30 Dezember 2020. Bd. 194. DOI 10.1016/j.envres.2020.110679. Verfügbar unter: https://irf.fhnw.ch/handle/11654/32398