Abstract
BackgroundIn vitro systems have inherent limitations in their ability to model whole organism gene responses, which must be identified and appropriately considered when developing predictive biomarkers of in vivo toxicity. Systematic comparison of in vitro and in vivo temporal gene expression profiles were conducted to assess the ability of Hepa1c1c7 mouse hepatoma cells to model hepatic responses in C57BL/6 mice following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).ResultsGene expression analysis and functional gene annotation indicate that Hepa1c1c7 cells appropriately modeled the induction of xenobiotic metabolism genes in vivo. However, responses associated with cell cycle progression and proliferation were unique to Hepa1c1c7 cells, consistent with the cell cycle arrest effects of TCDD on rapidly dividing cells. In contrast, lipid metabolism and immune responses, representative of whole organism effects in vivo, were not replicated in Hepa1c1c7 cells.ConclusionThese results identified inherent differences in TCDD-mediated gene expression responses between these models and highlighted the limitations of in vitro systems in modeling whole organism responses, and additionally identified potential predictive biomarkers of toxicity.
Highlights
In vitro systems have inherent limitations in their ability to model whole organism gene responses, which must be identified and appropriately considered when developing predictive biomarkers of in vivo toxicity
Similar policies in the US, such as the ICCVAM Authorization Act of 2000, provide guidelines to facilitate the regulatory acceptance of alternative testing methods. These initiatives combined with the need to assess an expanding list of drug candidates and commercial chemicals for toxicity, have increased demand for the development and implementation of high-throughput in vitro screening assays that are predictive of toxicity in humans and ecologically-relevant species
In vitro microarray data analysis Temporal gene expression profiles were assessed in Hepa1c1c7 wild type cells following treatment with 10 nM TCDD using cDNA microarrays with 13,362 spotted features
Summary
In vitro systems have inherent limitations in their ability to model whole organism gene responses, which must be identified and appropriately considered when developing predictive biomarkers of in vivo toxicity. Advances in microarray and related technologies continue to revolutionize biomedical research and are being incorporated into toxicology and risk assessment These technologies facilitate a more comprehensive elucidation of the mechanisms of toxicity, and support mechanistically-based quantitative risk assessment [1,2,3,4,5]. Similar policies in the US, such as the ICCVAM Authorization Act of 2000, provide guidelines to facilitate the regulatory acceptance of alternative testing methods These initiatives combined with the need to assess an expanding list of drug candidates and commercial chemicals for toxicity, have increased demand for the development and implementation of high-throughput in vitro screening assays that are predictive of toxicity in humans and ecologically-relevant species
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