You are here:
DIFFERENTIAL EXPRESSION OF RETINOIC ACID BIOSYNTHETIC AND METABOLISM GENES IN LIVERS FROM MICE TREATED WITH HEPATOTUMORIGENIC AND NON-HEPATOTUMORIGENIC CONAZOLES
Citation:
CHEN, P., W. PADGETT, T. MOORE, S. D. HESTER, S. Y. THAI, W. M. WINNIK, AND S. NESNOW. DIFFERENTIAL EXPRESSION OF RETINOIC ACID BIOSYNTHETIC AND METABOLISM GENES IN LIVERS FROM MICE TREATED WITH HEPATOTUMORIGENIC AND NON-HEPATOTUMORIGENIC CONAZOLES. Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.
Description:
Conazoles are fungicides used in crop protection and as pharmaceuticals. Triadimefon and propiconazole are hepatotumorigenic in mice, while myclobutanil is not. Previous toxicogenomic studies suggest that alteration of the retinoic acid metabolism pathway may play a key event in conazole-induced hepatotumorigenesis. We have used quantitative real-time polymerase chain reaction (qRT-PCR) to examine the expression of specific genes associated with the biosynthesis, and metabolism of all trans retinoic acid (RA) in the livers from male CD-1 mice (3 per group). The mice were exposed to triadimefon (1800 ppm), propiconazole (2500 ppm) or myclobutanil (2000 ppm) in the feed for 4, 30 or 90 days. The genes examined were RA biosynthesis genes Bcmol (ß-carotene 15, 15¿-monooxygenase), Aoxl (aldehyde oxidase), Rdh9 (retinol dehydrogenase), and Aldh1a7 (aldehyde dehydrogenase); the RA catabolism gene CYP26a1 (retinoic acid hydroxylase); and the retinol transport and storage gene, Lrat (lecithin-retinol acyltransferase). CYP26a1 mRNA had increased expression by all three conazoles at the 4 and 30 day exposure times. Triadimefon induced the greatest mRNA expression of CYP26a1 at each time point (e.g. 9.6-, 11.6- and 2.1-fold induction vs. controls at day 4, 30 and 90, respectively). Aldh1a1 was upregulated, and Bcmol, Rdh9, and Lrat were down regulated by all three conazoles at selected time points. Aoxl was unaffected by conazole treatment. Overall, the transcriptional activities of Bcmol, Rdh9, and Lrat were correlated with temporal CYP2Ga1 expression for triadimefon and propiconazole. The induction of CYP26a1 and the associated down regulation of several RA biosynthesis genes and Lrat suggest that RA levels may be reduced in hepatic tissues by these conazoles. The consistent alteration of this pathway by the tumorigenic conazoles suggests that it might be a necessary event in conazole-induced hepatotumorigenesis.