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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jun 08, 2019 |
| Title |
Systems modeling of developmental vascular toxicity |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
More than 80,000 chemicals in commerce present a challenge for hazard assessments that toxicity testing in the 21st century strives to address through high-throughput screening (HTS) assays. Assessing chemical effects on human development adds an additional layer of complexity to the screening, with a need to capture complex and dynamic events essential for proper embryo-fetal development. HTS data from ToxCast/Tox21 informs systems toxicology models, which incorporate molecular targets and biological pathways into mechanistic models describing the effects of chemicals on human cells, 3D organotypic culture models, and small model organisms. Adverse Outcome Pathways (AOPs) provide a useful framework for integrating the evidence derived from these in silico and in vitro systems to inform chemical hazard characterization. To illustrate this formulation, we have built an AOP for developmental toxicity through a mode of action linked to embryonic vascular disruption (Aop43). Here, we review the model for quantitative prediction of developmental vascular toxicity from ToxCast HTS data and compare the HTS results to functional vascular development assays in complex cell systems, virtual tissues, and small model organisms. ToxCast HTS predictions from several published and unpublished assays covering different aspects of the angiogenic cycle were generated for a test set of 38 chemicals representing a range of putative vascular disrupting compounds (pVDCs). Results boost confidence in the capacity to predict adverse developmental outcomes from HTS in vitro data and model computational dynamics for in silico reconstruction of developmental systems biology. Finally, we demonstrate the integration of the AOP and developmental systems toxicology to investigate the unique modes of action of two angiogenesis inhibitors.
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| Overall design |
Rat whole embryo cultures were exposed to 5HPP-33 (5, 15, 30 µM), TNP-470 (0.25, 2.5, 25 µM), or culture medium control. At four hours post-culture, the visceral yolk sac (VYS) was separated from the embryo and RNA was extracted from each embryo (n = 8/concentration) or from pooled VYSs ( n = 4/concentration) for RNA-seq analysis.
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| Contributor(s) |
Saili KS, Franzosa JA, Baker NC, Ellis-Hutchings RG, Settivari RS, Carney EW, Spencer RM, Zurlinden TJ, Kleinstreuer NC, Li S, Xia M, Knudsen TB |
| Citation |
Katerine S. Saili, Jill A. Franzosa, Nancy C. Baker, Robert G. Ellis-Hutchings, Raja S. Settivari, Edward W. Carney, Richard M. Spencer, Todd J. Zurlinden, Nicole C. Kleinstreuer, Shuaizhang Li, Menghang Xia and Thomas B. Knudsen. Systems modeling of developmental vascular toxicity. Current Opinion in Toxicology 2019;15:55-63. doi:10.1016/j.cotox.2019.04.004
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| Submission date |
Jun 07, 2019 |
| Last update date |
Sep 09, 2019 |
| Contact name |
Thomas Knudsen |
| E-mail(s) |
knudsen.thomas@epa.gov
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| Phone |
5704364895
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| Organization name |
U.S. EPA
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| Street address |
109 T.W. Alexander Drive
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| City |
RTP |
| State/province |
North Carolina |
| ZIP/Postal code |
27711 |
| Country |
USA |
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| Platforms (1) |
| GPL14844 |
Illumina HiSeq 2000 (Rattus norvegicus) |
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| Samples (84)
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| Relations |
| BioProject |
PRJNA547772 |
| SRA |
SRP200769 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE132375_RAW.tar |
62.6 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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