Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 220, Issue 3, Pages 284-291Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2007.01.018
Keywords
arsenic; In utero exposure; fetal liver; gene expression; estrogen signaling; steroid metabolism
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Funding
- Intramural NIH HHS [NIH0011069698] Funding Source: Medline
- NCI NIH HHS [N01-CO-12400, N01CO12400] Funding Source: Medline
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Exposure to inorganic arsenic in utero in OH mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p < 0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17 beta-hydroxysteroid dehydrogenase-7 (HSD17 beta 7; involved in estradiol production) and decreased expression of HSD17 beta 5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-la, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. Published by Elsevier Inc.
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