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. 2007 Jul 1;236(1-2):7-15.
doi: 10.1016/j.tox.2007.03.021. Epub 2007 Mar 31.

Aberrant DNA methylation and gene expression in livers of newborn mice transplacentally exposed to a hepatocarcinogenic dose of inorganic arsenic

Yaxiong Xie  1 , Jie Liu, Lamia Benbrahim-Tallaa, Jerry M Ward, Daniel Logsdon, Bhalchandra A Diwan, Michael P Waalkes
Affiliations

Aberrant DNA methylation and gene expression in livers of newborn mice transplacentally exposed to a hepatocarcinogenic dose of inorganic arsenic

Yaxiong Xie et al. Toxicology. .

Abstract

Our prior work showed that brief exposure of pregnant C3H mice to inorganic arsenic-induced hepatocellular carcinoma (HCC) formation in adult male offspring. The current study examined the early hepatic events associated with this oncogenic transformation. Pregnant mice were exposed to a known carcinogenic dose of arsenic (85 ppm) in the drinking water from gestation days 8 to 18. The dams were allowed to give birth and liver samples from newborn males were analyzed for arsenic content, global DNA methylation and aberrant expression of genes relevant to the carcinogenic process. Arsenic content in newborn liver reached 57 ng/g wet weight, indicating arsenic had crossed the placenta, reached the fetal liver and that significant amounts remained after birth. Global methylation status of hepatic DNA was not altered by arsenic in the newborn. However, a significant reduction in methylation occurred globally in GC-rich regions. Microarray and real-time RT-PCR analysis showed that arsenic exposure enhanced expression of genes encoding for glutathione production and caused aberrant expression of genes related to insulin growth factor signaling pathways and cytochrome P450 enzymes. Other expression alterations observed in the arsenic-treated male mouse newborn liver included the overexpression of cdk-inhibitors and stress response genes including increased expression of metallothionein-1 and decreased expression of betaine-homocysteine methyltransferase and thioether S-methyltransferase. Thus, transplacental exposure to arsenic at a hepatocarcinogenic dose induces alterations in DNA methylation and a complex set of aberrant gene expressions in the newborn liver, a target of arsenic carcinogenesis.

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Figures

Fig. 1
Fig. 1
Effect of in utero arsenic exposure on the global methylation status in newborn mouse liver by the methyl acceptance assay. Data are mean ± S.E.M. (n = 6).
Fig. 2
Fig. 2
Effect of in utero arsenic exposure on the methylation of the CG-rich regions in newborn mouse liver by restrictive DNA digestion and PCR amplification of CG-rich regions. Upper panel: representative gel electrophoresis images; lower panel: quantification of the indicated band with Image J software. Data are mean ± S.E.M. of three experiments. *Significantly different from controls, p < 0.05. Arrow indicates the bands of interest.
Fig. 3
Fig. 3
Effect of in utero arsenic exposure on glutathione and stress-related gene expression in newborn mouse liver. Data are mean ± S.E.M. (n = 6). *Significantly different from controls, p < 0.05.
Fig. 4
Fig. 4
Effect of in utero arsenic exposure on expression of genes related to cytochrome P450 enzymes and the IGF signaling systems. Data are mean ± S.E.M. (n = 6). *Significantly different from controls p < 0.05.
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