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Arch Toxicol. 2019 Aug;93(8):2219-2235. doi: 10.1007/s00204-019-02505-7. Epub 2019 Jul 5.

Genome-wide promoter DNA methylation profiling of hepatocellular carcinomas arising either spontaneously or due to chronic exposure to Ginkgo biloba extract (GBE) in B6C3F1/N mice.

Author information

1
Experimental Pathology Laboratories, Inc., Research Triangle Park, NC, USA.
2
Cellular and Molecular Pathology Branch, Division of National Toxicology Program (DNTP), National Institute of Environmental Health Sciences (NIEHS), 111 T.W. Alexander Drive, Research Triangle Park, NC, 27709, USA.
3
Global Scientific and Regulatory Affairs, The Coca-Cola Company, 1 Coca Cola Plaza, NW, Atlanta, GA, USA.
4
Sciome LLC, Research Triangle Park, NC, USA.
5
In Vivo Animal Core, Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
6
Cellular and Molecular Pathology Branch, Division of National Toxicology Program (DNTP), National Institute of Environmental Health Sciences (NIEHS), 111 T.W. Alexander Drive, Research Triangle Park, NC, 27709, USA. arun.pandiri@nih.gov.

Abstract

Epigenetic modifications, such as DNA methylation, play an important role in carcinogenesis. In a recent NTP study, chronic exposure of B6C3F1/N mice to Ginkgo biloba extract (GBE) resulted in a high incidence of hepatocellular carcinomas (HCC). Genome-wide promoter methylation profiling on GBE-exposed HCC (2000 mg/kg group), spontaneous HCC (vehicle-control group), and age-matched vehicle control liver was performed to identify differentially methylated genes in GBE-exposed HCC and spontaneous HCC. DNA methylation alterations were correlated to the corresponding global gene expression changes. Compared to control liver, 1296 gene promoters (719 hypermethylated, 577 hypomethylated) in GBE-exposed HCC and 738 (427 hypermethylated, 311 hypomethylated) gene promoters in spontaneous HCC were significantly differentially methylated, suggesting an impact of methylation on GBE-exposed HCC. Differential methylation of promoter regions in relevant cancer genes (cMyc, Spry2, Dusp5) and their corresponding differential gene expression was validated by quantitative pyrosequencing and qRT-PCR, respectively. In conclusion, we have identified differentially methylated promoter regions of relevant cancer genes altered in GBE-exposed HCC compared to spontaneous HCC. Further study of unique sets of differentially methylated genes in chemical-exposed mouse HCC could potentially be used to differentiate treatment-related tumors from spontaneous-tumors in cancer bioassays and provide additional understanding of the underlying epigenetic mechanisms of chemical carcinogenesis.

KEYWORDS:

B6C3F1/N mice; DNA methylation; Ginkgo biloba extract; Hepatocellular carcinoma

PMID:
31278416
DOI:
10.1007/s00204-019-02505-7

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