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.
Highlights
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates a wide range of biological effects in response to endogenous and dietary ligands
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
In response to 3MC or other AHR agonists, the AHR translocates to the nucleus where it heterodimerizes with AHR nuclear translocator (ARNT) and the complex binds to AHR response elements (AHREs) located in the 5 regulatory region of hundreds of genes, including cytochrome P450 1A1 (CYP1A1), CYP1B1, and TCDD-inducible poly-ADP-ribose-polymerase (TIPARP) [1,2]
Summary
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates a wide range of biological effects in response to endogenous and dietary ligands. Toxicological effects are induced upon activation by numerous environmental and synthetic ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAHs) such as 3-methylcholanthrene (3MC) [1]. Tiparp−/− and hepatocyte-specific Tiparp−/− mice treated with a normally non-lethal dose of 10 μg/kg TCDD exhibit increased sensitivity to TCDD-induced toxicities including the development of steatohepatitis, hepatotoxicity, and lethal wasting syndrome [13,24]. No 3MC-treated Tiparp−/− mice survived beyond day 16 This increased sensitivity to 3MC-induced lethality was not due to severe hepatotoxicity or wasting syndrome, but rather the mice exhibited a chylous ascites condition characterized by the peritoneal accumulation of a viscous fluid with high lipid and protein content. Our data show that TIPARP has an important role in modulating the differential toxic effects of two distinct AHR ligands, and further characterize it as a key regulator of the AHR signaling pathway
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