Development and validation of a high-throughput transcriptomic biomarker to address 21st century genetic toxicology needs.
Proc Natl Acad Sci U S A
; 114(51): E10881-E10889, 2017 12 19.
Article
en En
| MEDLINE
| ID: mdl-29203651
ABSTRACT
Interpretation of positive genotoxicity findings using the current in vitro testing battery is a major challenge to industry and regulatory agencies. These tests, especially mammalian cell assays, have high sensitivity but suffer from low specificity, leading to high rates of irrelevant positive findings (i.e., positive results in vitro that are not relevant to human cancer hazard). We developed an in vitro transcriptomic biomarker-based approach that provides biological relevance to positive genotoxicity assay data, particularly for in vitro chromosome damage assays, and propose its application for assessing the relevance of the in vitro positive results to carcinogenic hazard. The transcriptomic biomarker TGx-DDI (previously known as TGx-28.65) readily distinguishes DNA damage-inducing (DDI) agents from non-DDI agents. In this study, we demonstrated the ability of the biomarker to classify 45 test agents across a broad set of chemical classes as DDI or non-DDI. Furthermore, we assessed the biomarker's utility in derisking known irrelevant positive agents and evaluated its performance across analytical platforms. We correctly classified 90% (9 of 10) of chemicals with irrelevant positive findings in in vitro chromosome damage assays as negative. We developed a standardized experimental and analytical protocol for our transcriptomics biomarker, as well as an enhanced application of TGx-DDI for high-throughput cell-based genotoxicity testing using nCounter technology. This biomarker can be integrated in genetic hazard assessment as a follow-up to positive chromosome damage findings. In addition, we propose how it might be used in chemical screening and assessment. This approach offers an opportunity to significantly improve risk assessment and reduce cost.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Biomarcadores
/
Perfilación de la Expresión Génica
/
Ensayos Analíticos de Alto Rendimiento
/
Transcriptoma
/
Pruebas de Mutagenicidad
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2017
Tipo del documento:
Article