Grouping of UVCB substances with dose-response transcriptomics data from human cell-based assays

John S House, Fabian A Grimm, William D Klaren, Abigail Dalzell, Srikeerthana Kuchi, Shu-Dong Zhang, Klaus Lenz, Peter J Boogard, Hans B Ketelslegers, Timothy W Gant, Ivan Rusyn, Fred A Wright

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Abstract

The application of in vitro biological assays as new approach methodologies (NAMs) to support grouping of UVCB (unknown or variable composition, complex reaction products and biological materials) substances has recently been demonstrated. In addition to cell-based phenotyping as NAMs, in vitro transcriptomic profiling is used for deeper mechanistic understanding of biological responses to chemicals and to support grouping and read-across. However, the value of gene expression profiling for characterizing complex substances like UVCBs has not been explored. Using 141 petroleum substance extracts, we performed dose-response transcriptomic profiling in human induced pluripotent stem cell (iPSC)-derived hepatocytes, cardiomyocytes, neurons, and endothelial cells, as well as cell lines MCF7 and A375. The goal was to determine whether transcriptomic data can be used to group these UVCBs, and to further characterize the molecular basis for in vitro biological responses. We found distinct transcriptional responses for petroleum substances by manufacturing class. Pathway enrichment informed interpretation of effects of substances and UVCB petroleum-class. Transcriptional activity was strongly correlated with concentration of polycyclic aromatic compounds (PAC), especially in iPSC-derived hepatocytes. Supervised analysis using transcriptomics, alone or in combination with bioactivity data collected on these same substances/cells, suggest that transcriptomics data provide useful mechanistic information, but only modest additional value for grouping. Overall, these results further demonstrate the value of NAMs for grouping of UVCBs, identify informative cell lines, and provide data that could be used for justifying selection of substances for further testing that may be required for registration.

Original languageEnglish
Number of pages16
JournalALTEX
Early online date10 Mar 2022
DOIs
Publication statusE-pub ahead of print - 10 Mar 2022

Bibliographical note

This work was funded by a contract with Concawe (Brussels, Belgium). IR, FAW and WDK were partially supported by the National Institute of Environmental Health Sciences grants P42 ES027704 and T32 ES026568. TWG was partially supported by the National Institute of Health Research, Health Protection Research Unit, Environmental Exposures and Health held with Imperial College, London, UK.

Keywords

  • iPSC cell lines
  • petroleum
  • dose-response
  • NAMs
  • read-across

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