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Mutagenicity of acrylamide and glycidamide in human TP53 knock-in (Hupki) mouse embryo fibroblasts
- Source :
- Archives of Toxicology
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Acrylamide is a suspected human carcinogen formed during high-temperature cooking of starch-rich foods. It is metabolised by cytochrome P450 2E1 to its reactive metabolite glycidamide, which forms pre-mutagenic DNA adducts. Using the human TP53 knock-in (Hupki) mouse embryo fibroblasts (HUFs) immortalisation assay (HIMA), acrylamide- and glycidamide-induced mutagenesis was studied in the tumour suppressor gene TP53. Selected immortalised HUF clones were also subjected to next-generation sequencing to determine mutations across the whole genome. The TP53-mutant frequency after glycidamide exposure (1.1 mM for 24 h, n = 198) was 9% compared with 0% in cultures treated with acrylamide [1.5 (n = 24) or 3 mM (n = 6) for 48 h] and untreated vehicle (water) controls (n = 36). Most glycidamide-induced mutations occurred at adenines with A > T/T > A and A > G/T > C mutations being the most common types. Mutations induced by glycidamide occurred at specific TP53 codons that have also been found to be mutated in human tumours (i.e., breast, ovary, colorectal, and lung) previously associated with acrylamide exposure. The spectrum of TP53 mutations was further reflected by the mutations detected by whole-genome sequencing (WGS) and a distinct WGS mutational signature was found in HUF clones treated with glycidamide that was again characterised by A > G/T > C and A > T/T > A mutations. The WGS mutational signature showed similarities with COSMIC mutational signatures SBS3 and 25 previously found in human tumours (e.g., breast and ovary), while the adenine component was similar to COSMIC SBS4 found mostly in smokers’ lung cancer. In contrast, in acrylamide-treated HUF clones, only culture-related background WGS mutational signatures were observed. In summary, the results of the present study suggest that glycidamide may be involved in the development of breast, ovarian, and lung cancer.
- Subjects :
- 0301 basic medicine
Health, Toxicology and Mutagenesis
DNA Mutational Analysis
Ovary
Genotoxicity and Carcinogenicity
Toxicology
medicine.disease_cause
Cell Line
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine
Animals
Humans
TP53
Gene Knock-In Techniques
Carcinogen
Whole genome sequencing
Whole-genome sequencing
Acrylamide
Mutation
Whole Genome Sequencing
Chemistry
Mutagenesis
Dietary carcinogen
DNA adducts
Embryo
General Medicine
Fibroblasts
Molecular biology
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
030220 oncology & carcinogenesis
Epoxy Compounds
Tumor Suppressor Protein p53
DNA
Mutagens
Subjects
Details
- ISSN :
- 14320738 and 03405761
- Volume :
- 94
- Database :
- OpenAIRE
- Journal :
- Archives of Toxicology
- Accession number :
- edsair.doi.dedup.....d76175055ea546e6fe1700dc8b777123