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Biological and Dose Thresholds for an Early Genomic Biomarker of Liver Carcinogenesis in Mice
Citation:
Hill, T., V. Bhat, AND C. Wood. Biological and Dose Thresholds for an Early Genomic Biomarker of Liver Carcinogenesis in Mice. OPENTOX USA 2017, Durham, NC, July 12 - 13, 2017.
Impact/Purpose:
Short-term changes in molecular biomarkers are a central component of strategies to rapidly identify and prospectively model health effects of environmental chemicals. The overall aim of this work is to investigate whether genomic effect thresholds can be used to predict later-life outcomes across chemical space. This information will support efforts by EPA to prioritize chemicals for further testing based on early effects and assess potential carcinogenic modes of action more efficiently. Broad goals of this work are to better integrate apical and genomic data streams, inform chemical screening efforts, and develop systematic ways to identify biological significance or adversity based on genomic data.
Description:
Traditional data sources for cancer risk assessment are resource-intensive, retrospective, and not feasible for the vast majority of environmental chemicals. The use of quantitative short-term genomic biomarkers may streamline this process by providing protective limits for known pathways of chemical carcinogenesis. In this study we examined biological and dose thresholds for the Cyp2b10 gene marker of constitutive androstane receptor (CAR) activation in mice. Sustained CAR activation is an established mitogenic pathway in the liver and the most common mode of action evaluated by the U.S. EPA. Liver Cyp2b10 expression at 7 days (fold-change vs. respective control group), cell proliferation at 7 days (labeling index), and tumor incidence at 18-24 months were analyzed across five established CAR-activating liver carcinogens previously tested in male mice: Cyproconazole, Nitrapyrin, Pronamide, Sulfoxaflor, and Tetraconazole. Statistically significant dose relationships (p<0.05) were identified by Pearson’s correlation, supporting calculation of hypothetical tumorigenic thresholds using linear regression. Benchmark dose (BMD) estimation was then used to compare Cyp2b10 and tumor incidence dose potencies within each chemical. A mean Cyp2b10 induction threshold of 69 (SEM ± 22, range 31 - 136) corresponded to a significant increase in liver tumor incidence at p<0.05. Similarly, a Cyp2b10 induction threshold of 65 (SEM ± 16, range 33 - 120) corresponded to the hypothetical tumorigenic threshold for liver cell proliferation within each chemical. Overall, BMD estimates for Cyp2b10 induction were 2.6 times higher (SEM ± 1.1, range 0.2 - 6.5) than BMD estimates for tumor incidence. These findings support the idea that early genomic changes can be used to establish threshold estimates or “molecular tipping points” that are predictive of later-life outcomes. Future work in this area will inform efforts to incorporate new data types into cancer risk assessment. This abstract does not necessarily represent the views or policies of the U.S. EPA.