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. 2009 Dec 21;266(1-3):6-15.
doi: 10.1016/j.tox.2009.10.004. Epub 2009 Oct 12.

Transcriptional changes associated with reduced spontaneous liver tumor incidence in mice chronically exposed to high dose arsenic

Gail M Nelson  1 , Gene J Ahlborn, James W Allen, Hongzu Ren, J Christopher Corton, Michael P Waalkes, Kirk T Kitchin, Bhalchandra A Diwan, Geremy Knapp, Don A Delker
Affiliations

Transcriptional changes associated with reduced spontaneous liver tumor incidence in mice chronically exposed to high dose arsenic

Gail M Nelson et al. Toxicology. .

Abstract

Exposure of male C3H mice in utero (from gestational days 8-18) to 85ppm sodium arsenite via the dams' drinking water has previously been shown to increase liver tumor incidence by 2 years of age. However, in our companion study (Ahlborn et al., 2009), continuous exposure to 85ppm sodium arsenic (from gestational day 8 to postnatal day 365) did not result in increased tumor incidence, but rather in a significant reduction (0% tumor incidence). The purpose of the present study was to examine the gene expression responses that may lead to the apparent protective effect of continuous arsenic exposure. Genes in many functional categories including cellular growth and proliferation, gene expression, cell death, oxidative stress, protein ubiquitination, and mitochondrial dysfunction were altered by continuous arsenic treatment. Many of these genes are known to be involved in liver cancer. One such gene associated with rodent hepatocarcinogenesis, Scd1, encodes stearoyl-CoA desaturase and was down-regulated by continuous arsenic treatment. An overlap between the genes in our study affected by continuous arsenic exposure and those from the literature affected by long-term caloric restriction suggests that reduction in the spontaneous tumor incidence under both conditions may involve similar gene pathways such as fatty acid metabolism, apoptosis, and stress response.

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Conflict of interest statement

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Fig. 1.
Fig. 1.
Venn diagram of number of hepatic probe sets significantly altered relative to the untreated control by the arsenic treatment regimens.
Fig. 2.
Fig. 2.
Fold-change expression relative to control for selected genes.
Fig. 2.
Fig. 2.
Fold-change expression relative to control for selected genes.
Fig. 3.
Fig. 3.
Insulin receptor signaling pathway (from Ingenuity Pathways Analysis) with gene expression significantly different from the control (up: red; down: green) shown for the continuous treatment group. An asterisk denotes multiple identifiers in the dataset mapped to that single gene (replicates). Expression shown (as color intensity) is for the highest fold-change (absolute value) replicate.
Fig. 4.
Fig. 4.
Glycolysis and lipogenesis pathways with gene expression significantly different from the control (up: red; down: green) shown for the continuous treatment group. Regulated genes are listed beside their respective nuclear transcription factors. An asterisk denotes multiple identifiers in the dataset mapped to that single gene (replicates). Expression shown (as color intensity) is for the highest fold-change (absolute value) replicate.
Fig. 5.
Fig. 5.
qRT-PCR results for the Scd1 gene. Each value represents the average of three replicate reactions of four unique samples. Values were calculated using a relative standard curve method and normalized to the log of the amount of input RNA. An asterisk indicates statistical significance in comparison to the untreated control sample (t-test, p≤0.05).
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