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Grouping of UVCB substances with dose-response transcriptomics data from human cell-based assays
John S House1,2, Fabian A Grimm3, William D Klaren3,4
1Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
ALTEX
|March 15, 2022
Summary
New approach methodologies (NAMs) using transcriptomic profiling effectively characterized petroleum substances, aiding in grouping complex chemicals. Gene expression data provided mechanistic insights but limited additional grouping value beyond bioactivity data.
Area of Science:
- Toxicology and Chemical Safety
- Genomics and Bioinformatics
- In Vitro Assays
Background:
- In vitro biological assays, including cell-based phenotyping and transcriptomic profiling, are emerging as New Approach Methodologies (NAMs).
- These NAMs support the grouping and read-across of substances with unknown or variable composition, complex reaction products, and biological materials (UVCBs).
- The utility of gene expression profiling for characterizing complex UVCB substances remains underexplored.
Purpose of the Study:
- To evaluate the potential of dose-response transcriptomic profiling for grouping 141 petroleum substance extracts.
- To characterize the molecular mechanisms underlying in vitro biological responses to these complex substances.
- To assess the added value of transcriptomics for UVCB grouping compared to bioactivity data.
Main Methods:
- Dose-response transcriptomic profiling was conducted on human induced pluripotent stem cell (iPSC)-derived hepatocytes, cardiomyocytes, neurons, endothelial cells, and MCF7 and A375 cell lines.
- Analysis included pathway enrichment to interpret biological effects and correlation analysis with polycyclic aromatic compounds (PACs).
- Supervised analysis combined transcriptomics with bioactivity data for grouping assessment.
Main Results:
- Distinct transcriptional responses were observed for petroleum substances categorized by manufacturing class.
- Transcriptional activity correlated strongly with polycyclic aromatic compound (PAC) concentration, particularly in iPSC-derived hepatocytes.
- Transcriptomics provided mechanistic information but offered only modest additional value for grouping when combined with bioactivity data.
Conclusions:
- Transcriptomic profiling is valuable for characterizing complex UVCB substances and understanding their biological responses.
- The study identified informative cell lines for UVCB assessment and highlighted the utility of NAMs for chemical grouping.
- Findings support the use of transcriptomics in justifying substance selection for further regulatory testing.
