3-Methylcholanthrene Induces Chylous Ascites and Lethality in Tiparp Knockout Mice

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-regulated transcription factor that is activated upon binding to various ligands. The activated AHR modulates the expression of many genes including cytochrome P450s (CYPs) such as Cyp1a1, Cyp1b1, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (Tiparp). We recently reported that TIPARP is a transcriptional repressor of AHR and Tiparp knockout mice show increased sensitivity to dioxin-induced toxicities. Because of these findings, we examined the sensitivity of Tiparp knockout mice to 3-methylcholanthrene (3-MC), another potent AHR ligand. Tiparp knockout mice treated with 100mg/kg of 3-MC exhibited increased hepatotoxicity, increased lipolysis, and developed chylous ascites compared with treated wildtype mice. No treated Tiparp knockout mice survived beyond day 16; all wildtype mice survived the 30 day treatment. Collectively, this thesis shows that Tiparp knockout mice exhibit increased sensitivity to 3-MC-induced toxicity and lethality supporting our previous findings that TIPARP is an important negative regulator of AHR activity.