Rager J. 2016. Integration of high-content and high-throughput screening data to inform hexavalent chromium mode of action. Environmental Mutagenesis and Genomics Society, September 26, Kansas City, KS.
Hexavalent chromium (Cr(VI)) is a widely studied chemical with large amounts of data available for informing chemical mode-of-action (MOA). This robust knowledgebase uniquely positions Cr(VI) to serve as an important case study in developing methods to integrate high-throughput methodologies into chemical risk assessment. In vivo high-content screening (HCS) data have been produced in mice exposed to varying concentrations of Cr(VI) via drinking water. These data have been used to investigate transcriptomic responses in the duodenum, the primary site for Cr(VI)-induced cancer in mice following oral exposure. In vitro high-throughput screening (HTS) data from the Tox21 consortium has also been generated for Cr(VI) in various cell lines. This study aimed to integrate these HCS/HTS data with toxicological data surrounding Cr(VI)-induced intestinal tumors in the mouse model. Dose-response modeling of HCS and HTS data identified both gene-specific and pathway-level responses involved in Cr(VI) toxicity, while providing critical information regarding the sequence of events and doses at which events likely occur. Of particular relevance to elucidating Cr(VI) MOA, responses related to apoptosis and cell proliferation were calculated with lower benchmark doses and higher enrichment frequencies in comparison to those involved in DNA damage response signaling. These findings suggest that key events related to cytotoxicity and hyperplasia are likely some of the most sensitive responses to Cr(VI) exposure, and thus should be considered in health and safety evaluations. Findings from this study contribute to the currently evolving strategies for synthesizing relevant HCS/HTS data from in vivo and in vitro testing.