Mutagenicity of N-hydroxy-4-aminobiphenyl in human TP53 knock-in (Hupki) mouse embryo fibroblasts
© 2021 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagen Society..
TP53 harbors somatic mutations in more than half of human tumors with some showing characteristic mutation spectra that have been linked to environmental exposures. In bladder cancer, a unique distribution of mutations amongst several codons of TP53 has been hypothesized to be caused by environmental carcinogens including 4-aminobiphenyl (4-ABP). 4-ABP undergoes metabolic activation to N-hydroxy-4-aminobiphenyl (N-OH-4-ABP) and forms pre-mutagenic adducts in DNA, of which N-(deoxyguanosin-8-yl)-4-ABP (dG-C8-4-ABP) is the major one. Human TP53 knock-in mouse embryo fibroblasts (HUFs) are a useful model to study the influence of environmental carcinogens on TP53-mutagenesis. By performing the HUF immortalization assay (HIMA) TP53-mutant HUFs are generated and mutations can be identified by sequencing. Here we studied the induction of mutations in human TP53 after treatment of primary HUFs with N-OH-4-ABP. In addition, mutagenicity in the bacterial lacZ reporter gene and the formation of dG-C8-4-ABP, measured by 32 P-postlabelling analysis, were determined in N-OH-4-ABP-treated primary HUFs. A total of 6% TP53-mutants were identified after treatment with 40 μM N-OH-4-ABP for 24 hr (n = 150) with G>C/C>G transversion being the main mutation type. The mutation spectrum found in the TP53 gene of immortalized N-OH-4-ABP-treated HUFs was unlike the one found in human bladder cancer. DNA adduct formation (~40 adducts/108 nucleotides) was detected after 24 hr treatment with 40 μM N-OH-4-ABP, but lacZ mutagenicity was not observed. Adduct levels decreased substantially (sixfold) after a 24 hr recovery period indicating that primary HUFs can efficiently repair the dG-C8-4-ABP adduct possibly before mutations are fixed. In conclusion, the observed difference in the N-OH-4-ABP-induced TP53 mutation spectrum to that observed in human bladder tumors do not support a role of 4-ABP in human bladder cancer development.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
|---|---|
| Enthalten in: |
Environmental and molecular mutagenesis - 62(2021), 4 vom: 10. Apr., Seite 252-264 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Hölzl-Armstrong, Lisa [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 29.11.2021 Date Revised 29.11.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1002/em.22429 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM32179222X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM32179222X | ||
| 003 | DE-627 | ||
| 005 | 20231225180637.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/em.22429 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1072.xml |
| 035 | |a (DE-627)NLM32179222X | ||
| 035 | |a (NLM)33620775 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Hölzl-Armstrong, Lisa |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mutagenicity of N-hydroxy-4-aminobiphenyl in human TP53 knock-in (Hupki) mouse embryo fibroblasts |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.11.2021 | ||
| 500 | |a Date Revised 29.11.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagen Society. | ||
| 520 | |a TP53 harbors somatic mutations in more than half of human tumors with some showing characteristic mutation spectra that have been linked to environmental exposures. In bladder cancer, a unique distribution of mutations amongst several codons of TP53 has been hypothesized to be caused by environmental carcinogens including 4-aminobiphenyl (4-ABP). 4-ABP undergoes metabolic activation to N-hydroxy-4-aminobiphenyl (N-OH-4-ABP) and forms pre-mutagenic adducts in DNA, of which N-(deoxyguanosin-8-yl)-4-ABP (dG-C8-4-ABP) is the major one. Human TP53 knock-in mouse embryo fibroblasts (HUFs) are a useful model to study the influence of environmental carcinogens on TP53-mutagenesis. By performing the HUF immortalization assay (HIMA) TP53-mutant HUFs are generated and mutations can be identified by sequencing. Here we studied the induction of mutations in human TP53 after treatment of primary HUFs with N-OH-4-ABP. In addition, mutagenicity in the bacterial lacZ reporter gene and the formation of dG-C8-4-ABP, measured by 32 P-postlabelling analysis, were determined in N-OH-4-ABP-treated primary HUFs. A total of 6% TP53-mutants were identified after treatment with 40 μM N-OH-4-ABP for 24 hr (n = 150) with G>C/C>G transversion being the main mutation type. The mutation spectrum found in the TP53 gene of immortalized N-OH-4-ABP-treated HUFs was unlike the one found in human bladder cancer. DNA adduct formation (~40 adducts/108 nucleotides) was detected after 24 hr treatment with 40 μM N-OH-4-ABP, but lacZ mutagenicity was not observed. Adduct levels decreased substantially (sixfold) after a 24 hr recovery period indicating that primary HUFs can efficiently repair the dG-C8-4-ABP adduct possibly before mutations are fixed. In conclusion, the observed difference in the N-OH-4-ABP-induced TP53 mutation spectrum to that observed in human bladder tumors do not support a role of 4-ABP in human bladder cancer development | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a 4-aminobiphenyl | |
| 650 | 4 | |a DNA adducts | |
| 650 | 4 | |a TP53 | |
| 650 | 4 | |a bladder carcinogen | |
| 650 | 4 | |a mutation | |
| 650 | 7 | |a Aminobiphenyl Compounds |2 NLM | |
| 650 | 7 | |a DNA Adducts |2 NLM | |
| 650 | 7 | |a Mutagens |2 NLM | |
| 650 | 7 | |a TP53 protein, human |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a N-hydroxy-4-aminobiphenyl |2 NLM | |
| 650 | 7 | |a 6810-26-0 |2 NLM | |
| 700 | 1 | |a Kucab, Jill E |e verfasserin |4 aut | |
| 700 | 1 | |a Zwart, Edwin P |e verfasserin |4 aut | |
| 700 | 1 | |a Luijten, Mirjam |e verfasserin |4 aut | |
| 700 | 1 | |a Phillips, David H |e verfasserin |4 aut | |
| 700 | 1 | |a Arlt, Volker M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Environmental and molecular mutagenesis |d 1987 |g 62(2021), 4 vom: 10. Apr., Seite 252-264 |w (DE-627)NLM01291066X |x 1098-2280 |7 nnns |
| 773 | 1 | 8 | |g volume:62 |g year:2021 |g number:4 |g day:10 |g month:04 |g pages:252-264 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/em.22429 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 62 |j 2021 |e 4 |b 10 |c 04 |h 252-264 | ||