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. 2017 Jul 1;158(1):199-212.
doi: 10.1093/toxsci/kfx085.

High-Throughput Screening Data Interpretation in the Context of In Vivo Transcriptomic Responses to Oral Cr(VI) Exposure

Julia E Rager  1 , Caroline L Ring  1 , Rebecca C Fry  2   3 , Mina Suh  4 , Deborah M Proctor  4 , Laurie C Haws  1 , Mark A Harris  5 , Chad M Thompson  5
Affiliations

High-Throughput Screening Data Interpretation in the Context of In Vivo Transcriptomic Responses to Oral Cr(VI) Exposure

Julia E Rager et al. Toxicol Sci. .

Abstract

The toxicity of hexavalent chromium [Cr(VI)] in drinking water has been studied extensively, and available in vivo and in vitro studies provide a robust dataset for application of advanced toxicological tools to inform the mode of action (MOA). This study aimed to contribute to the understanding of Cr(VI) MOA by evaluating high-throughput screening (HTS) data and other in vitro data relevant to Cr(VI), and comparing these findings to robust in vivo data, including transcriptomic profiles in target tissues. Evaluation of Tox21 HTS data for Cr(VI) identified 11 active assay endpoints relevant to the Ten Key Characteristics of Carcinogens (TKCCs) that have been proposed by other investigators. Four of these endpoints were related to TP53 (tumor protein 53) activation mapping to genotoxicity (KCC#2), and four were related to cell death/proliferation (KCC#10). HTS results were consistent with other in vitro data from the Comparative Toxicogenomics Database. In vitro responses were compared to in vivo transcriptomic responses in the most sensitive target tissue, the duodenum, of mice exposed to ≤ 180 ppm Cr(VI) for 7 and 90 days. Pathways that were altered both in vitro and in vivo included those relevant to cell death/proliferation. In contrast, pathways relevant to p53/DNA damage were identified in vitro but not in vivo. Benchmark dose modeling and phenotypic anchoring of in vivo transcriptomic responses strengthened the finding that Cr(VI) causes cell stress/injury followed by proliferation in the mouse duodenum at high doses. These findings contribute to the body of evidence supporting a non-mutagenic MOA for Cr(VI)-induced intestinal cancer.

Keywords: dose–response modeling; hexavalent chromium; high-throughput screening; mode of action; risk assessment; transcriptomics.

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Figures

Figure 1
Figure 1
Genes with differential expression associated with exposure to Cr(VI) in the mouse duodenum. The number of DEGs identified by comparing exposed versus unexposed samples (FC ≥ 2, q < 0.05) after (A) 7 days and (B) 90 days of exposure to varying concentrations of Cr(VI) (as SDD in drinking water). DEGs that showed both differential expression in exposed versus unexposed samples (FC ≥ 2, q < 0.05) and dose-dependent changes in expression identified through BMD modeling (curve fit p > .10) after (C) 7 days and (D) 90 days of exposure to Cr(VI). Heat maps display fold change (FC) in expression (exposed/unexposed) for each DEG, with the concentrations of SDD (in mg/l) listed on the top.
Figure 2
Figure 2
Apoptosis and p53 signaling related to Cr(VI) exposure. Molecules altered by in vitro exposure to Cr(VI), as identified through HTS Tox21 data and CTD, are enriched for (A) apoptosis signaling and (C) p53 signaling. Genes showing dose-dependent changes in expression after 90 days of exposure to Cr(VI) in the mouse duodenum are enriched for (B) apoptosis signaling but not (D) p53 signaling. No genes relevant to p53/DNA damage signaling within the canonical apoptosis pathway showed altered expression in vivo, as marked by the red asterisks. Note that pathways associated with 7 days of exposure to Cr(VI) in the mouse duodenum are not displayed, as there was no enrichment for apoptosis or p53 signaling in these tissues.
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