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ToxSci Advance Access published online on January 4, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj091
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received November 22, 2005
Accepted December 28, 2005

Carcinogenicity

Diethanolamine and Phenobarbital Produce an Altered Pattern of Methylation in GC-Rich Regions of DNA in B6C3F1 Mouse Hepatocytes Similar to that Resulting from Choline Deficiency

Ammie N. Bachman 1, Lisa M. Kamendulis 2, and Jay I. Goodman 1 *

1 Department of Pharmacology and Toxicology, Michigan State Univ., East Lansing, MI, 48824
2 Department of Pharmacology and Toxicology, Indiana Univ. School of Medicine, Indianapolis, IN 46202

* To whom correspondence should be addressed.
Jay I. Goodman, E-mail: goodman3{at}msu.edu


  Abstract

DNA methylation is an epigenetic mechanism regulating transcription, which when disrupted, can alter gene expression and contribute to carcinogenesis. Diethanolamine (DEA), a non-genotoxic alkanolamine, produces liver tumors in mice. Studies suggest DEA inhibits choline uptake and causes biochemical changes consistent with choline deficiency (CD). Rodents fed methyl-deficient diets exhibit altered methylation of hepatic DNA and an increase in liver tumors, e.g., CD causes liver tumors in B6C3F1 mice. We hypothesize that DEA-induced CD leads to altered methylation patterns which facilitates tumorigenesis. B6C3F1 hepatocytes in primary culture were grown in the presence of either 4.5mM DEA, 3mM Phenobarbital (PB) or CD media for 48hrs. These concentrations induced comparable increases in DNA synthesis. PB, a nongenotoxic rodent liver carcinogen known to alter methylation in mouse liver, was included as a positive control. Global, average, DNA methylation status was not affected. The methylation status of GC-rich regions of DNA, which are often associated with promoter regions, were assessed via methylation-sensitive restriction digestion and arbitrarily primed PCR with capillary electrophoretic separation and detection of PCR products. DEA, PB and CD treatments resulted in 54, 63, and 54 regions of altered methylation (RAMs), respectively, and the majority were hypomethylations. A high proportion of RAMs (72%) were identical when DEA was compared to CD. Similarly, 70% were identical between PB and CD. Altered patterns of methylation in GC-rich regions induced by DEA and PB resemble that of CD and indicate that altered DNA methylation is an epigenetic mechanism involved in the facilitation of mouse liver tumorigenesis.

Keywords: DNA methylation; Diethanolamine; Choline Deficiency; Phenobarbital; GC-rich Regions.
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