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Time-course Interactions between Cell Proliferation and DNA Sequence Variants in a Mouse Model of Latent Carcinogenicity
Citation:
Wood, C., W. Ward, B. Chorley, G. Carswell, A. Fisher, A. DeAngelo, AND S. Hester. Time-course Interactions between Cell Proliferation and DNA Sequence Variants in a Mouse Model of Latent Carcinogenicity. Society of Toxicology, New Orleans, LA, March 13 - 17, 2016.
Impact/Purpose:
In this case study we investigate the interaction between an early epigenetic event (cell proliferation) and later genetic event (sequence variants) in a mouse model of cancer. This work supports goals of Task 1.1g: Adverse Outcome Pathway Descriptions for Cancer within the AOP Discovery and Development Project (12.01) of the Chemical Safety for Sustainability (CSS) Program. The “small p” product for this task is a portfolio of case studies that highlight novel strategies for developing cancer pathways based on early key event biomarkers.
Description:
A fundamental principle of non-mutagenic chemical carcinogenesis is that increased cell proliferation enhances spontaneous DNA damage. Over time, this damage drives mutations in oncogenic genes that ultimately lead to cancer. This concept is a central part of cancer mode of action evaluation, although few studies have quantitatively tested this idea. Here, we used a mouse model of latent carcinogenicity to examine interactions between cell proliferation and DNA sequence variants over time. The treatment for this study was dichloroacetic acid (DCA), an oxidative metabolic agent that induces liver tumors in mice in the absence of direct short-term mutagenic effects. Male B6C3F1 mice 4 weeks of age were treated with deionized water (dH20; control); 3.5 g/l DCA continuously; or 3.5 g/l DCA for 10 weeks followed by control dH20. We predicted that variants would increase with age and that DCA treatment would amplify this effect. Sequence variants in liver DNA were evaluated in 1348 target loci across 65 key cancer-related genes at 14, 30, 56, and 82 weeks of age using the Illumina TruSeq amplicon platform for targeted resequencing (n=4/group). Incidence of hepatocellular adenoma or carcinoma was higher in the continuous DCA (44/44, 100%) and prior DCA (34/55, 62%) groups compared to controls (19/52, 37%) (P<0.01 for both). Liver cell proliferation (labeling index) was modestly higher after 10 weeks of DCA treatment (P=0.01) but not at any subsequent time points, decreasing with age in all groups. At the 82-week time point, total variant counts were higher in continuous DCA (n=200) and prior DCA (n=174) groups compared to controls (n=99) (P<0.001 for both). However, absolute variant counts did not increase with age in any group. These findings support the idea that early-life epigenetic changes can lead to later-life genetic effects related to cancer. This abstract does not reflect EPA policy.