Particulate and drug-induced toxicity assessed in novel quadruple cell human primary hepatic disease models of steatosis and pre-fibrotic NASH
In an effort to replace, reduce and refine animal experimentation, there is an unmet need to advance current in vitro models that offer features with physiological relevance and enhanced predictivity of in vivo toxicological output. Hepatic toxicology is key following chemical, drug and nanomaterial...
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Published in | Archives of toxicology Vol. 96; no. 1; pp. 287 - 303 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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Berlin/Heidelberg
Springer Berlin Heidelberg
01.01.2022
Springer Nature B.V |
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Abstract | In an effort to replace, reduce and refine animal experimentation, there is an unmet need to advance current in vitro models that offer features with physiological relevance and enhanced predictivity of in vivo toxicological output. Hepatic toxicology is key following chemical, drug and nanomaterials (NMs) exposure, as the liver is vital in metabolic detoxification of chemicals as well as being a major site of xenobiotic accumulation (i.e., low solubility particulates). With the ever-increasing production of NMs, there is a necessity to evaluate the probability of consequential adverse effects, not only in health but also in clinically asymptomatic liver, as part of risk stratification strategies. In this study, two unique disease initiation and maintenance protocols were developed and utilised to mimic steatosis and pre-fibrotic NASH in scaffold-free 3D liver microtissues (MT) composed of primary human hepatocytes, hepatic stellate cells, Kupffer cells and sinusoidal endothelial cells. The characterized diseased MT were utilized for the toxicological assessment of a panel of xenobiotics. Highlights from the study included: 1. Clear experimental evidence for the pre-existing liver disease is important in the augmentation of xenobiotic-induced hepatotoxicity and 2. NMs are able to activate stellate cells. The data demonstrated that pre-existing disease is vital in the intensification of xenobiotic-induced liver damage. Therefore, it is imperative that all stages of the wide spectrum of liver disease are incorporated in risk assessment strategies. This is of significant consequence, as a substantial number of the general population suffer from sub-clinical liver injury without any apparent or diagnosed manifestations. |
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AbstractList | In an effort to replace, reduce and refine animal experimentation, there is an unmet need to advance current in vitro models that offer features with physiological relevance and enhanced predictivity of in vivo toxicological output. Hepatic toxicology is key following chemical, drug and nanomaterials (NMs) exposure, as the liver is vital in metabolic detoxification of chemicals as well as being a major site of xenobiotic accumulation (i.e., low solubility particulates). With the ever-increasing production of NMs, there is a necessity to evaluate the probability of consequential adverse effects, not only in health but also in clinically asymptomatic liver, as part of risk stratification strategies. In this study, two unique disease initiation and maintenance protocols were developed and utilised to mimic steatosis and pre-fibrotic NASH in scaffold-free 3D liver microtissues (MT) composed of primary human hepatocytes, hepatic stellate cells, Kupffer cells and sinusoidal endothelial cells. The characterized diseased MT were utilized for the toxicological assessment of a panel of xenobiotics. Highlights from the study included: 1. Clear experimental evidence for the pre-existing liver disease is important in the augmentation of xenobiotic-induced hepatotoxicity and 2. NMs are able to activate stellate cells. The data demonstrated that pre-existing disease is vital in the intensification of xenobiotic-induced liver damage. Therefore, it is imperative that all stages of the wide spectrum of liver disease are incorporated in risk assessment strategies. This is of significant consequence, as a substantial number of the general population suffer from sub-clinical liver injury without any apparent or diagnosed manifestations. |
Author | Hutter, Simon Pawlowska, Agnieszka Valli, Jessica Kermanizadeh, Ali Moritz, Wolfgang Sanchez, Katarzyna Whyte, Graeme Stone, Vicki |
Author_xml | – sequence: 1 givenname: Ali orcidid: 0000-0002-2989-9078 surname: Kermanizadeh fullname: Kermanizadeh, Ali email: A.Kermanizadeh@derby.ac.uk organization: Human Sciences Research Centre, University of Derby, School of Engineering and Physical Sciences, Heriot Watt University – sequence: 2 givenname: Jessica surname: Valli fullname: Valli, Jessica organization: School of Engineering and Physical Sciences, Heriot Watt University – sequence: 3 givenname: Katarzyna surname: Sanchez fullname: Sanchez, Katarzyna organization: InSphero AG – sequence: 4 givenname: Simon surname: Hutter fullname: Hutter, Simon organization: InSphero AG – sequence: 5 givenname: Agnieszka surname: Pawlowska fullname: Pawlowska, Agnieszka organization: InSphero AG – sequence: 6 givenname: Graeme surname: Whyte fullname: Whyte, Graeme organization: School of Engineering and Physical Sciences, Heriot Watt University – sequence: 7 givenname: Wolfgang surname: Moritz fullname: Moritz, Wolfgang organization: InSphero AG – sequence: 8 givenname: Vicki surname: Stone fullname: Stone, Vicki organization: School of Engineering and Physical Sciences, Heriot Watt University |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34668024$$D View this record in MEDLINE/PubMed |
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CitedBy_id | crossref_primary_10_1080_10937404_2023_2261848 crossref_primary_10_1016_j_phymed_2023_154911 crossref_primary_10_3390_nano12111810 crossref_primary_10_1002_smll_202200231 crossref_primary_10_1080_10937404_2022_2153456 crossref_primary_10_1186_s12989_022_00508_4 |
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Keywords | In vitro hepatotoxicity Pre-existing disease state In vitro vs. in vivo relevance NASH 3D primary human quadruple-cell liver microtissue model Steatosis |
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SubjectTerms | Animal research Biocompatibility Biomedical and Life Sciences Biomedicine Detoxification Endothelial cells Environmental Health Experimentation Fatty liver Fibrosis Health risks Hepatocytes Hepatotoxicity In Vitro Systems Kupffer cells Liver Liver diseases Nanomaterials Nanotechnology Occupational Medicine/Industrial Medicine Particulates Pharmacology/Toxicology Risk assessment Steatosis Stellate cells Toxicity Toxicology Xenobiotics |
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Title | Particulate and drug-induced toxicity assessed in novel quadruple cell human primary hepatic disease models of steatosis and pre-fibrotic NASH |
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