Classification of Developmental Toxicants in a Human iPSC Transcriptomics-Based Test

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2022
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Cherianidou, Anna
Seidel, Florian
Kappenberg, Franziska
Blüthgen, Nils
Meisig, Johannes
Hengstler, Jan G.
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Chemical Research in Toxicology. American Chemical Society (ACS). 2022, 35(5), pp. 760-773. ISSN 0893-228X. eISSN 1520-5010. Available under: doi: 10.1021/acs.chemrestox.1c00392
Zusammenfassung

Despite the progress made in developmental toxicology, there is a great need for in vitro tests that identify developmental toxicants in relation to human oral doses and blood concentrations. In the present study, we established the hiPSC-based UKK2 in vitro test and analyzed genome-wide expression profiles of 23 known teratogens and 16 non-teratogens. Compounds were analyzed at the maximal plasma concentration (Cmax) and at 20-fold Cmax for a 24 h incubation period in three independent experiments. Based on the 1000 probe sets with the highest variance and including information on cytotoxicity, penalized logistic regression with leave-one-out cross-validation was used to classify the compounds as test-positive or test-negative, reaching an area under the curve (AUC), accuracy, sensitivity, and specificity of 0.96, 0.92, 0.96, and 0.88, respectively. Omitting the cytotoxicity information reduced the test performance to an AUC of 0.94, an accuracy of 0.79, and a sensitivity of 0.74. A second method, which used the number of significantly deregulated probe sets to classify the compounds, resulted in a specificity of 1; however, the AUC (0.90), accuracy (0.90), and sensitivity (0.83) were inferior compared to those of the logistic regression-based procedure. Finally, no increased performance was achieved when the high test concentrations (20-fold Cmax) were used, in comparison to testing within the realistic clinical range (1-fold Cmax). In conclusion, although further optimization is required, for example, by including additional readouts and cell systems that model different developmental processes, the UKK2-test in its present form can support the early discovery-phase detection of human developmental toxicants.

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ISO 690CHERIANIDOU, Anna, Florian SEIDEL, Franziska KAPPENBERG, Nadine DRESER, Jonathan BLUM, Tanja WALDMANN, Nils BLÜTHGEN, Johannes MEISIG, Marcel LEIST, Jan G. HENGSTLER, 2022. Classification of Developmental Toxicants in a Human iPSC Transcriptomics-Based Test. In: Chemical Research in Toxicology. American Chemical Society (ACS). 2022, 35(5), pp. 760-773. ISSN 0893-228X. eISSN 1520-5010. Available under: doi: 10.1021/acs.chemrestox.1c00392
BibTex
@article{Cherianidou2022Class-57281,
  year={2022},
  doi={10.1021/acs.chemrestox.1c00392},
  title={Classification of Developmental Toxicants in a Human iPSC Transcriptomics-Based Test},
  number={5},
  volume={35},
  issn={0893-228X},
  journal={Chemical Research in Toxicology},
  pages={760--773},
  author={Cherianidou, Anna and Seidel, Florian and Kappenberg, Franziska and Dreser, Nadine and Blum, Jonathan and Waldmann, Tanja and Blüthgen, Nils and Meisig, Johannes and Leist, Marcel and Hengstler, Jan G.}
}
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