Unlocking the power of transcriptomic biomarkers in qualitative and quantitative genotoxicity assessment of chemicals with TempO-Seq

In the realm of toxicology, assessing the potential genotoxicity of chemicals is crucial for safeguarding human health and the environment. Traditionally, such assessments have relied heavily on animal testing, raising ethical concerns and posing limitations in terms of human relevance and scalability. To address these challenges, researchers at Vrije Universiteit Brussel have been exploring new approach methodologies (NAMs) that leverage advanced technologies to provide human-relevant dose-response data. In a groundbreaking study, scientists investigated the integration of two transcriptomic biomarkers, GENOMARK and TGx-DDI, to enhance genotoxicity assessment and potency ranking.

Transcriptomic biomarkers offer a promising avenue for evaluating genotoxicity by analyzing gene expression patterns in response to chemical exposure. GENOMARK and TGx-DDI, two such biomarkers, have demonstrated high accuracy in classifying genotoxic hazards. However, as they were derived from different training sets, researchers sought to determine whether integrating these biomarkers could provide complementary information, thus strengthening genotoxicity assessment.

To evaluate the efficacy of integrating GENOMARK and TGx-DDI, the researchers utilized a human-derived metabolically competent cell line known as HepaRG. These cells were exposed to varying concentrations of 10 chemicals, including both known genotoxicants and non-genotoxicants, for 72 hours. Gene expression data were then generated using TempO-Seq, a high-throughput transcriptomic technology, to assess the applicability of GENOMARK to this platform.

The study yielded promising results, with GENOMARK demonstrating a prediction performance of 100% when applied to TempO-Seq, affirming its suitability for high-throughput transcriptomic analysis. Subsequent comparison between GENOMARK and TGx-DDI revealed a high concordance in hazard classification and potency ranking for identified genotoxic chemicals. This underscores the value of integrating these NAMs in a weight of evidence evaluation of genotoxicity, offering a more comprehensive and accurate approach to assessing chemical hazards.

The integration of transcriptomic biomarkers such as GENOMARK and TGx-DDI represents a significant advancement in genotoxicity assessment, paving the way for more effective and human-relevant methodologies. By leveraging innovative technologies and harnessing the complementary information provided by these biomarkers, researchers can enhance the accuracy and reliability of chemical hazard identification and potency ranking. Ultimately, such advancements contribute to the ongoing efforts to modernize toxicological testing practices and promote the development of safer and more sustainable products for the benefit of society.

Thienpont A, Cho E, Williams A, Meier MJ, Yauk CL, Rogiers V, Vanhaecke T, Mertens B. (2024) Unlocking the Power of Transcriptomic Biomarkers in Qualitative and Quantitative Genotoxicity Assessment of Chemicals. Chem Res Toxicol [Epub ahead of print]. [article]

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