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CAR and PXR-dependent transcriptional changes in the mouse liver after exposure to propiconazole
Citation:
CORTON, C., S. D. HESTER, L. M. Aleksunes, H. Ren, C. Jones, T. Moore, C. D. Klaassen, AND S. NESNOW. CAR and PXR-dependent transcriptional changes in the mouse liver after exposure to propiconazole. Presented at Society of Toxicology 49th Annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
To test the hypothesis that CAR and PXR mediate many of the transcriptional changes after propiconazole treatment, we exposed wild-type, CAR-null and PXR-null mice to vehicle or propiconazole (210 mglkg/day) by gavage for 7 days and examined gene expression by Affymetrix full-genome gene chips.
Description:
Exposure to the conazoles propiconazole and triadimefon but not myclobutanilled to tumors in mice after 2 years. Transcript profiling studies in the livers ofwild-type mice after short-term exposure to the conazoles revealed signatures indicating the involvement ofthe nuclear receptors CAR and PXR. To test the hypothesis that CAR and PXR mediate many ofthe transcriptional changes after propiconazole treatment, we exposed wild-type, CAR-null and PXR-null mice to vehicle or propiconazole (210 mglkg/day) by gavage for 7 days and examined gene expression by Affymetrix full-genome gene chips. PXR and CAR genotype had profound effects on the transcript profiles. About 85% ofall ofthe genes regulated by propiconazole in wild-type mice were dependent on PXR and included those involved in cholesterol biosynthesis. The behavior ofthe remaining -15% ofthe genes significantly overlapped with those regulated by the CAR activators, phenobarbital or TCPOBOP in wild-type but not CAR-null mouse livers. Transcript profiling ofthe livers from wild-type and CAR-null mice revealed that -79% ofall genes regulated by propiconazole were dependent on CAR. The CAR-independent genes included many xenobiotic metabolizing genes that are known to be regulated by PXR. Although no changes in serum cholesterol levels were observed in treated compared to untreated mice, CARnull and PXR-null mice exhibited higher serum cholesterol levels than wild-type mice, indicating the role ofthese nuclear receptors in cholesterol homeostasis. Overall, these results indicate the importance ofboth CAR and PXR in the transcriptional effects ofpropiconazole. (This abstract does not necessarily reflect US EPA policy).