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3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice.

Abstract

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp-/- mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp-/- mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp-/- or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP's role as a repressor of AHR signaling, 3MC-treated Tiparp-/- mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp-/- mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp-/- mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp-/- mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp-/- mice. Our study reveals that Tiparp-/- mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.

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  • Authors+Show Affiliations

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    Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. tiffany.cho@mail.utoronto.ca.

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    Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. debb.bott@gmail.com.

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    Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. shaimaa.ahmed1@gmail.com.

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    Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. dhutin1@gmail.com.

    ,

    Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. alvin_v_gomez@yahoo.com.

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    Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. Laura.Tamblyn@uhnresearch.ca.

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    Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. angel.zhou@mail.utoronto.ca.

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    Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. tania.watts@utoronto.ca.

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    Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. denis.grant@utoronto.ca.

    Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. Jason.matthews@medisin.uio.no. Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. Jason.matthews@medisin.uio.no.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31083300

    Citation

    Cho, Tiffany E., et al. "3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice." International Journal of Molecular Sciences, vol. 20, no. 9, 2019.
    Cho TE, Bott D, Ahmed S, et al. 3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice. Int J Mol Sci. 2019;20(9).
    Cho, T. E., Bott, D., Ahmed, S., Hutin, D., Gomez, A., Tamblyn, L., ... Matthews, J. (2019). 3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice. International Journal of Molecular Sciences, 20(9), doi:10.3390/ijms20092312.
    Cho TE, et al. 3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice. Int J Mol Sci. 2019 May 10;20(9) PubMed PMID: 31083300.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice. AU - Cho,Tiffany E, AU - Bott,Debbie, AU - Ahmed,Shaimaa, AU - Hutin,David, AU - Gomez,Alvin, AU - Tamblyn,Laura, AU - Zhou,Angela C, AU - Watts,Tania H, AU - Grant,Denis M, AU - Matthews,Jason, Y1 - 2019/05/10/ PY - 2019/04/16/received PY - 2019/05/06/revised PY - 2019/05/07/accepted PY - 2019/5/15/entrez PY - 2019/5/15/pubmed PY - 2019/5/15/medline KW - 2,3,7,8-tetrachlorodibenzo-p-dioxin KW - 3-methylcholanthrene KW - TCDD-inducible poly-ADP-ribose polymerase (TIPARP) KW - chylous ascites KW - wasting syndrome JF - International journal of molecular sciences JO - Int J Mol Sci VL - 20 IS - 9 N2 - TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp-/- mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp-/- mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp-/- or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP's role as a repressor of AHR signaling, 3MC-treated Tiparp-/- mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp-/- mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp-/- mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp-/- mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp-/- mice. Our study reveals that Tiparp-/- mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/31083300/3-Methylcholanthrene_Induces_Chylous_Ascites_in_TCDD-Inducible_Poly-ADP-Ribose_Polymerase_(Tiparp)_Knockout_Mice L2 - http://www.mdpi.com/resolver?pii=ijms20092312 DB - PRIME DP - Unbound Medicine ER -