Unlocking the Power of Transcriptomic Biomarkers in Qualitative and Quantitative Genotoxicity Assessment of Chemicals
To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose–response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high classification accuracy for genotoxicity. As these bio...
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| Published in | Chemical research in toxicology Vol. 37; no. 3; pp. 465 - 475 |
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| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
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United States
American Chemical Society
18.03.2024
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| Abstract | To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose–response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high classification accuracy for genotoxicity. As these biomarkers were extracted from different training sets, we investigated whether combining the two biomarkers in a human-derived metabolically competent cell line (i.e., HepaRG) provides complementary information for the classification of genotoxic hazard identification and potency ranking. First, the applicability of GENOMARK to TempO-Seq, a high-throughput transcriptomic technology, was evaluated. HepaRG cells were exposed for 72 h to increasing concentrations of 10 chemicals (i.e., eight known in vivo genotoxicants and two in vivo nongenotoxicants). Gene expression data were generated using the TempO-Seq technology. We found a prediction performance of 100%, confirming the applicability of GENOMARK to TempO-Seq. Classification using TGx-DDI was then compared to GENOMARK. For the chemicals identified as genotoxic, benchmark concentration modeling was conducted to perform potency ranking. The high concordance observed for both hazard classification and potency ranking by GENOMARK and TGx-DDI highlights the value of integrating these NAMs in a weight of evidence evaluation of genotoxicity. |
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| AbstractList | To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose–response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high classification accuracy for genotoxicity. As these biomarkers were extracted from different training sets, we investigated whether combining the two biomarkers in a human-derived metabolically competent cell line (i.e., HepaRG) provides complementary information for the classification of genotoxic hazard identification and potency ranking. First, the applicability of GENOMARK to TempO-Seq, a high-throughput transcriptomic technology, was evaluated. HepaRG cells were exposed for 72 h to increasing concentrations of 10 chemicals (i.e., eight known in vivo genotoxicants and two in vivo nongenotoxicants). Gene expression data were generated using the TempO-Seq technology. We found a prediction performance of 100%, confirming the applicability of GENOMARK to TempO-Seq. Classification using TGx-DDI was then compared to GENOMARK. For the chemicals identified as genotoxic, benchmark concentration modeling was conducted to perform potency ranking. The high concordance observed for both hazard classification and potency ranking by GENOMARK and TGx-DDI highlights the value of integrating these NAMs in a weight of evidence evaluation of genotoxicity. To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose–response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high classification accuracy for genotoxicity. As these biomarkers were extracted from different training sets, we investigated whether combining the two biomarkers in a human-derived metabolically competent cell line (i.e., HepaRG) provides complementary information for the classification of genotoxic hazard identification and potency ranking. First, the applicability of GENOMARK to TempO-Seq, a high-throughput transcriptomic technology, was evaluated. HepaRG cells were exposed for 72 h to increasing concentrations of 10 chemicals (i.e., eight known in vivo genotoxicants and two in vivo nongenotoxicants). Gene expression data were generated using the TempO-Seq technology. We found a prediction performance of 100%, confirming the applicability of GENOMARK to TempO-Seq. Classification using TGx-DDI was then compared to GENOMARK. For the chemicals identified as genotoxic, benchmark concentration modeling was conducted to perform potency ranking. The high concordance observed for both hazard classification and potency ranking by GENOMARK and TGx-DDI highlights the value of integrating these NAMs in a weight of evidence evaluation of genotoxicity. To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose-response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high classification accuracy for genotoxicity. As these biomarkers were extracted from different training sets, we investigated whether combining the two biomarkers in a human-derived metabolically competent cell line (i.e., HepaRG) provides complementary information for the classification of genotoxic hazard identification and potency ranking. First, the applicability of GENOMARK to TempO-Seq, a high-throughput transcriptomic technology, was evaluated. HepaRG cells were exposed for 72 h to increasing concentrations of 10 chemicals (i.e., eight known genotoxicants and two nongenotoxicants). Gene expression data were generated using the TempO-Seq technology. We found a prediction performance of 100%, confirming the applicability of GENOMARK to TempO-Seq. Classification using TGx-DDI was then compared to GENOMARK. For the chemicals identified as genotoxic, benchmark concentration modeling was conducted to perform potency ranking. The high concordance observed for both hazard classification and potency ranking by GENOMARK and TGx-DDI highlights the value of integrating these NAMs in a weight of evidence evaluation of genotoxicity. To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose-response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high classification accuracy for genotoxicity. As these biomarkers were extracted from different training sets, we investigated whether combining the two biomarkers in a human-derived metabolically competent cell line (i.e., HepaRG) provides complementary information for the classification of genotoxic hazard identification and potency ranking. First, the applicability of GENOMARK to TempO-Seq, a high-throughput transcriptomic technology, was evaluated. HepaRG cells were exposed for 72 h to increasing concentrations of 10 chemicals (i.e., eight known in vivo genotoxicants and two in vivo nongenotoxicants). Gene expression data were generated using the TempO-Seq technology. We found a prediction performance of 100%, confirming the applicability of GENOMARK to TempO-Seq. Classification using TGx-DDI was then compared to GENOMARK. For the chemicals identified as genotoxic, benchmark concentration modeling was conducted to perform potency ranking. The high concordance observed for both hazard classification and potency ranking by GENOMARK and TGx-DDI highlights the value of integrating these NAMs in a weight of evidence evaluation of genotoxicity.To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose-response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high classification accuracy for genotoxicity. As these biomarkers were extracted from different training sets, we investigated whether combining the two biomarkers in a human-derived metabolically competent cell line (i.e., HepaRG) provides complementary information for the classification of genotoxic hazard identification and potency ranking. First, the applicability of GENOMARK to TempO-Seq, a high-throughput transcriptomic technology, was evaluated. HepaRG cells were exposed for 72 h to increasing concentrations of 10 chemicals (i.e., eight known in vivo genotoxicants and two in vivo nongenotoxicants). Gene expression data were generated using the TempO-Seq technology. We found a prediction performance of 100%, confirming the applicability of GENOMARK to TempO-Seq. Classification using TGx-DDI was then compared to GENOMARK. For the chemicals identified as genotoxic, benchmark concentration modeling was conducted to perform potency ranking. The high concordance observed for both hazard classification and potency ranking by GENOMARK and TGx-DDI highlights the value of integrating these NAMs in a weight of evidence evaluation of genotoxicity. |
| Author | Williams, Andrew Thienpont, Anouck Yauk, Carole L. Meier, Matthew J. Vanhaecke, Tamara Cho, Eunnara Rogiers, Vera Mertens, Birgit |
| AuthorAffiliation | Environmental Health Science and Research Bureau Department of Biology Department of Chemical and Physical Health Risks Department of In Vitro Toxicology and Dermato-Cosmetology University of Ottawa |
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| Snippet | To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose–response... To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose-response... To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose–response... |
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| Title | Unlocking the Power of Transcriptomic Biomarkers in Qualitative and Quantitative Genotoxicity Assessment of Chemicals |
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