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dc.contributor.authorHutin, D.
dc.contributor.authorTamblyn, L.
dc.contributor.authorGomez, A.
dc.contributor.authorGrimaldi, Giulia
dc.contributor.authorSoedling, H.
dc.contributor.authorCho, T.
dc.contributor.authorAhmed, S.
dc.contributor.authorLucas, C.
dc.contributor.authorKanduri, C.
dc.contributor.authorGrant, D.M.
dc.contributor.authorMatthews, J.
dc.date.accessioned2021-02-12T12:37:51Z
dc.date.available2021-02-12T12:37:51Z
dc.date.issued2018-10
dc.identifier.citationHutin D, Tamblyn L, Gomez A et al (2018) Hepatocyte-specific deletion of TIPARP, a negative regulator of the aryl hydrocarbon receptor, is sufficient to increase sensitivity to dioxin-induced wasting syndrome. Toxicological Sciences. 165(2): 347-360.en_US
dc.identifier.urihttp://hdl.handle.net/10454/18338
dc.descriptionYesen_US
dc.description.abstractThe aryl hydrocarbon receptor (AHR) mediates the toxic effects of dioxin (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin; TCDD), which includes thymic atrophy, steatohepatitis, and a lethal wasting syndrome in laboratory rodents. Although the mechanisms of dioxin toxicity remain unknown, AHR signaling in hepatocytes is necessary for dioxin-induced liver toxicity. We previously reported that loss of TCDD-inducible poly(adenosine diphosphate [ADP]-ribose) polymerase (TIPARP/PARP7/ARTD14), an AHR target gene and mono-ADP-ribosyltransferase, increases the sensitivity of mice to dioxin-induced toxicities. To test the hypothesis that TIPARP is a negative regulator of AHR signaling in hepatocytes, we generated Tiparpfl/fl mice in which exon 3 of Tiparp is flanked by loxP sites, followed by Cre-lox technology to create hepatocyte-specific (Tiparpfl/flCreAlb) and whole-body (Tiparpfl/flCreCMV; TiparpEx3−/−) Tiparp null mice. Tiparpfl/flCreAlb and TiparpEx3−/− mice given a single injection of 10 μg/kg dioxin did not survive beyond days 7 and 9, respectively, while all Tiparp+/+ mice survived the 30-day treatment. Dioxin-exposed Tiparpfl/flCreAlb and TiparpEx3−/− mice had increased steatohepatitis and hepatotoxicity as indicated by greater staining of neutral lipids and serum alanine aminotransferase activity than similarly treated wild-type mice. Tiparpfl/flCreAlb and TiparpEx3−/− mice exhibited augmented AHR signaling, denoted by increased dioxin-induced gene expression. Metabolomic studies revealed alterations in lipid and amino acid metabolism in liver extracts from Tiparpfl/flCreAlb mice compared with wild-type mice. Taken together, these data illustrate that TIPARP is an important negative regulator of AHR activity, and that its specific loss in hepatocytes is sufficient to increase sensitivity to dioxin-induced steatohepatitis and lethality.en_US
dc.description.sponsorshipThis work was supported by Canadian Institutes of Health Research (CIHR) operating grants (MOP-494265 and MOP-125919), CIHR New Investigator Award, an Early Researcher Award from the Ontario Ministry of Innovation (ER10-07-028), an unrestricted research grant from the DOW Chemical Company, the Johan Throne Holst Foundation, Novo Nordic Foundation and the Norwegian Cancer Society to J.M.en_US
dc.language.isoenen_US
dc.rights© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Reproduced in accordance with the publisher's self-archiving policy.en_US
dc.subjectAryl hydrocarbon receptoren_US
dc.subjectWasting syndromeen_US
dc.subjectADP-ribosylationen_US
dc.subject2, 3, 7, 8-tetrachlorodibenzo-p-dioxinen_US
dc.subjectTCDD-inducible poly-ADP-ribose polymeraseen_US
dc.titleHepatocyte-specific deletion of TIPARP, a negative regulator of the aryl hydrocarbon receptor, is sufficient to increase sensitivity to dioxin-induced wasting syndromeen_US
dc.status.refereedYesen_US
dc.date.Accepted2018
dc.date.application2018-06-04
dc.typeArticleen_US
dc.type.versionAccepted manuscripten_US
dc.identifier.doihttps://doi.org/10.1093/toxsci/kfy136
refterms.dateFOA2021-02-12T12:42:05Z
dc.openaccess.statusGreenen_US


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