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Effect of 2-acetylaminofluorene and its genotoxic metabolites on DNA adduct formation and DNA damage in 3D reconstructed human skin tissue models.
| Content Provider | Europe PMC |
|---|---|
| Author | Downs, Thomas R Arlt, Volker M Barnett, Brenda C Posgai, Ryan Pfuhler, Stefan |
| Copyright Year | 2019 |
| Abstract | In vitro genotoxicity assays utilising human skin models are becoming important tools for the safety assessment of chemicals whose primary exposure is via the dermal route. In order to explore metabolic competency and inducibility of CYP450 activating enzymes, 3D reconstructed human skin tissues were topically treated with 2-acetylaminofluorene (2-AAF) and its genotoxic metabolites, N-hydroxy-2-acetylaminofluorene (N-OH-2-AAF) and N-hydroxy-2-aminofluorene (N-OH-2-AF), which primarily cause DNA damage by forming DNA adducts. 2-AAF did not increase DNA damage measured in the reconstructed skin micronucleus (RSMN) assay when administered in multiple applications at 24 h intervals but was detected in the skin comet assay in the presence of the DNA polymerase inhibitor aphidicolin (APC). Similarly, no increase was found with N-OH-2-AAF in the RSMN assay after multiple treatments whereas a single 3 h exposure to N-OH-2-AAF caused a large dose-related increase in the skin comet assay. A significant increase in the RSMN assay was only obtained with the highly reactive N-OH-2-AF metabolite after multiple treatments over 72 h, whereas N-OH-2-AF caused a strong increase after a single 3 h exposure in the skin comet assay. In support of these results, DNA adduct formation, measured by the 32P-postlabelling assay, was examined. Adduct levels after 2-AAF treatment for 3 h were minimal but increased >10-fold after multiple exposures over 48 h, suggesting that enzyme(s) that metabolise 2-AAF are induced in the skin models. As expected, a single 3 h exposure to N-OH-2-AAF and N-OH-2-AF resulted in adduct levels that were at least 10-fold greater than those after multiple exposures to 2-AAF despite ~100-fold lower tested concentrations. Our results demonstrate that DNA damage caused by 2-AAF metabolites is more efficiently detected in the skin comet assay than the RSMN assay and after multiple exposures and enzyme induction, 2-AAF-induced DNA damage can be detected in the APC-modified comet assay. |
| Related Links | https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC8081378&blobtype=pdf |
| Page Count | 12 |
| ISSN | 02678357 |
| Volume Number | 36 |
| DOI | 10.1093/mutage/gez044 |
| PubMed Central reference number | PMC8081378 |
| Issue Number | 1 |
| PubMed reference number | 31816077 |
| Journal | Mutagenesis |
| e-ISSN | 14643804 |
| Language | English |
| Publisher | Oxford University Press |
| Publisher Date | 2021-04-01 |
| Publisher Place | United Kingdom |
| Access Restriction | Open |
| Rights License | This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com © The Author(s) 2019. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Health, Toxicology and Mutagenesis Toxicology Genetics (clinical) |
