ArticleArchives of toxicology2024
Evaluating the mutagenicity of N-nitrosodimethylamine in 2D and 3D HepaRG cell cultures using error-corrected next generation sequencing.
Article in Archives of toxicology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- The in vitro alkaline comet assay with liver models as a complementary tool for genotoxicity assessment of N-nitrosamines.Archives of toxicology · 2026Article
- Evaluating the Suitability of HepaRG Cells for Regulatory Micronucleus Testing: Comparing Results for a Diverse Set of 28 Chemicals to Regulatory Accepted TK6 Cells.Environmental and molecular mutagenesis · 2026Article
- N-nitrosodimethylamine induces cytochrome P450 activation but not epithelial remodeling in well-differentiated human airway epithelial cells.Cell biology and toxicology · 2026Article
- Mutagenicity of EAT-positive NDSRIs in HepaRG spheroids.NAM journal · 2026Article
- Application of the Comet Assay in Advanced In Vitro Models.Methods in molecular biology (Clifton, N.J.) · 2026Article
- The Alkaline Comet Assay for Assessment of DNA Damage.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Application of error-corrected sequencing technologies for in vivo regulatory mutagenicity assessment.Regulatory toxicology and pharmacology : RTP · 2026Review
- Genotoxicity evaluation of ten nitrosamine drug substance-related impurities using 2D and 3D HepaRG cell models.Regulatory toxicology and pharmacology : RTP · 2025Article
- Alignment between Duplex Sequencing and transgenic rodent mutation assay data in the assessment of in vivo NDMA-induced mutagenesis.Archives of toxicology · 2025Article
- Transferability, Reproducibility and Sensitivity of Mutation Quantification by Duplex Sequencing.Environmental and molecular mutagenesis · 2025Article
- Comparative DNA damage induced by eight nitrosamines in primary human and macaque hepatocytes.Chemico-biological interactions · 2025Article
- HepaRGNAM journal · 2025Article
- Mutation accumulation following extended exposure of human HepaRG cells to a genotoxic carcinogen.Journal of environmental science and health. Part C, Toxicology and carcinogenesis · 2025Article
- Optimizing the detection of N-nitrosamine mutagenicity in the Ames test.Regulatory toxicology and pharmacology : RTP · 2024Article
- Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses.Scientific reports · 2024Article
- Application of HepaRG cells for genotoxicity assessment: a review.Journal of environmental science and health. Part C, Toxicology and carcinogenesis · 2024Review
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human liver-derived metabolically competent HepaRG cells have been successfully employed in both two-dimensional (2D) and 3D spheroid formats for performing the comet assay and micronucleus (MN) assay. In the present study, we have investigated expanding the genotoxicity endpoints evaluated in HepaRG cells by detecting mutagenesis using two error-corrected next generation sequencing (ecNGS) technologies, Duplex Sequencing (DS) and High-Fidelity (HiFi) Sequencing. Both HepaRG 2D cells and 3D spheroids were exposed for 72 h to N-nitrosodimethylamine (NDMA), followed by an additional incubation for the fixation of induced mutations. NDMA-induced DNA damage, chromosomal damage, and mutagenesis were determined using the comet assay, MN assay, and ecNGS, respectively. The 72-h treatment with NDMA resulted in concentration-dependent increases in cytotoxicity, DNA damage, MN formation, and mutation frequency in both 2D and 3D cultures, with greater responses observed in the 3D spheroids compared to 2D cells. The mutational spectrum analysis showed that NDMA induced predominantly A:T → G:C transitions, along with a lower frequency of G:C → A:T transitions, and exhibited a different trinucleotide signature relative to the negative control. These results demonstrate that the HepaRG 2D cells and 3D spheroid models can be used for mutagenesis assessment using both DS and HiFi Sequencing, with the caveat that severe cytotoxic concentrations should be avoided when conducting DS. With further validation, the HepaRG 2D/3D system may become a powerful human-based metabolically competent platform for genotoxicity testing.
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