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Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation
Published on: June 17, 2015
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Transcriptomic characterization of C57BL/6 mouse embryonic stem cell differentiation and its modulation by
Xiugong Gao1, Jeffrey J Yourick1, Robert L Sprando1
1Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, Maryland, United States of America.
Plos One
|September 24, 2014
Summary
Embryonic stem cells (ESCs) offer a promising in vitro model for developmental toxicity testing. A defined "differentiation track" of gene expression in ESCs can identify compounds that disrupt normal embryonic development.
Area of Science:
- Developmental toxicology
- Stem cell biology
- Toxicology testing
Background:
- The Tox21 program promotes transitioning from traditional in vivo toxicology to higher throughput in vitro methods.
- Embryonic stem cells (ESCs) are a key alternative model for assessing developmental toxicity.
- Understanding gene expression during ESC differentiation is crucial for developing new toxicity assays.
Purpose of the Study:
- To characterize gene expression changes during mouse ESC differentiation.
- To investigate how developmental toxicants modulate these gene expression patterns.
- To establish a gene expression-based differentiation track for toxicity assessment.
Main Methods:
- Mouse ESCs were differentiated into embryoid bodies (EBs).
- RNA was collected from vehicle controls and compound-exposed EBs at various time points.
- Gene expression was analyzed using Affymetrix Mouse Gene 2.0 ST Array and subjected to Bonferroni-corrected statistical analysis.
- Gene Ontology (GO) and Principal Component Analysis (PCA) were employed to analyze gene expression data.
Main Results:
- 1996 genes were found to be differentially expressed during ESC differentiation.
- GO analysis revealed enrichment in differentiation-related processes, identifying biomarkers for all three germ layers.
- PCA demonstrated a chronological differentiation track for unexposed ESCs.
- Exposure to thalidomide, monobutyl phthalate, and valproic acid caused significant deviations from this differentiation track.
Conclusions:
- A defined gene expression differentiation track in ESCs can serve as a baseline for developmental toxicity testing.
- Significant deviations from this track indicate potential developmental toxicity.
- This ESC-based model offers a promising in vitro approach for assessing developmental toxicants.
