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Mechanistic investigations of DNA reactive carcinogens at low dose, through analysis of DNA adducts, mutations and DNA repair. / Adam David Thomas

Swansea University Author: Adam David Thomas

Abstract

Genetic toxicology assesses the genotoxic potential of chemicals in consumer products, pharmaceuticals and from agricultural and industrial processes. Such assessment is integral in hazard identification and risk assessment to prevent unnecessary human exposure and limit cancer risk. Human risk asse...

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Published: 2012
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa43089
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last_indexed 2019-10-21T16:49:00Z
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spelling 2018-08-29T15:39:33.5551132 v2 43089 2018-08-02 Mechanistic investigations of DNA reactive carcinogens at low dose, through analysis of DNA adducts, mutations and DNA repair. fab7e04239bbf899b6a51a97334e91b1 NULL Adam David Thomas Adam David Thomas true true 2018-08-02 Genetic toxicology assesses the genotoxic potential of chemicals in consumer products, pharmaceuticals and from agricultural and industrial processes. Such assessment is integral in hazard identification and risk assessment to prevent unnecessary human exposure and limit cancer risk. Human risk assessments for genotoxic alkylating agents were based upon linear dose-response models where genotoxicity accrues proportionally with dose. Evidence is accumulating to support a non-linear dose-response at low doses of ethyl methanesulfonate (EMS), a model alkylating agent. For acceptance of non-linear dose responses, a strong explanatory mechanism of action needs to be elucidated. In the following work, low dose mutagenic effects of methyl nitorosurea (MNU), the most potent alkylating agent, have been examined in AHH-1 human lymphoblastoid cells using the HPRT assay. An increase in mutant frequency was not observed until 0.01pg/ml MNU (LOGEL, Lowest Observed Genotoxic Effect Level) with a No-Observed Genotoxic Effect Level (NOGEL) at 0.0075pg/ml MNU. Of interest, is the apparent hormesis induced at 0.0025pg/ml MNU. The principle adduct responsible for MNU mutagenesis is 0 6Methylguanine (06MeG) that miscodes during replication and becomes fixed as GC->AT transitions. Accordingly, the non-linear increase in mutant frequency is accompanied by a non-linear increase in GC->AT transitions. Furthermore, evidence is provided that implicates methlyguanine methyltransferase (MGMT) in protecting DNA from MNU induced mutagenesis by repairing 0 6MeG at low doses, thereby creating the NOGEL. AHH-1 cells treated with 0 6Benzylguanine (06BG), to inactivate MGMT, were hypersensitive to low dose MNU mutagenesis. At 0.0075pg/ml MNU, there was a three-fold increase in mutant frequency and an increase in proportion of GC-^AT transitions, from 28% to 48% in MGMT inactivated cells. This thesis presents a non-linear dose-response for MNU with a strong biological mechanism of action involving DNA repair. E-Thesis Genotoxicity 31 12 2012 2012-12-31 COLLEGE NANME Swansea University Medical School COLLEGE CODE Swansea University Doctoral Ph.D 2018-08-29T15:39:33.5551132 2018-08-02T16:24:31.2566160 Swansea University Medical School Swansea University Medical School Adam David Thomas NULL 1 0043089-02082018162545.pdf 10821481.pdf 2018-08-02T16:25:45.7470000 Output 19345879 application/pdf E-Thesis true 2018-08-02T16:25:45.7470000 false
title Mechanistic investigations of DNA reactive carcinogens at low dose, through analysis of DNA adducts, mutations and DNA repair.
spellingShingle Mechanistic investigations of DNA reactive carcinogens at low dose, through analysis of DNA adducts, mutations and DNA repair.
Adam David Thomas
title_short Mechanistic investigations of DNA reactive carcinogens at low dose, through analysis of DNA adducts, mutations and DNA repair.
title_full Mechanistic investigations of DNA reactive carcinogens at low dose, through analysis of DNA adducts, mutations and DNA repair.
title_fullStr Mechanistic investigations of DNA reactive carcinogens at low dose, through analysis of DNA adducts, mutations and DNA repair.
title_full_unstemmed Mechanistic investigations of DNA reactive carcinogens at low dose, through analysis of DNA adducts, mutations and DNA repair.
title_sort Mechanistic investigations of DNA reactive carcinogens at low dose, through analysis of DNA adducts, mutations and DNA repair.
author_id_str_mv fab7e04239bbf899b6a51a97334e91b1
author_id_fullname_str_mv fab7e04239bbf899b6a51a97334e91b1_***_Adam David Thomas
author Adam David Thomas
author2 Adam David Thomas
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publishDate 2012
institution Swansea University
college_str Swansea University Medical School
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hierarchy_top_title Swansea University Medical School
hierarchy_parent_id swanseauniversitymedicalschool
hierarchy_parent_title Swansea University Medical School
department_str Swansea University Medical School{{{_:::_}}}Swansea University Medical School{{{_:::_}}}Swansea University Medical School
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description Genetic toxicology assesses the genotoxic potential of chemicals in consumer products, pharmaceuticals and from agricultural and industrial processes. Such assessment is integral in hazard identification and risk assessment to prevent unnecessary human exposure and limit cancer risk. Human risk assessments for genotoxic alkylating agents were based upon linear dose-response models where genotoxicity accrues proportionally with dose. Evidence is accumulating to support a non-linear dose-response at low doses of ethyl methanesulfonate (EMS), a model alkylating agent. For acceptance of non-linear dose responses, a strong explanatory mechanism of action needs to be elucidated. In the following work, low dose mutagenic effects of methyl nitorosurea (MNU), the most potent alkylating agent, have been examined in AHH-1 human lymphoblastoid cells using the HPRT assay. An increase in mutant frequency was not observed until 0.01pg/ml MNU (LOGEL, Lowest Observed Genotoxic Effect Level) with a No-Observed Genotoxic Effect Level (NOGEL) at 0.0075pg/ml MNU. Of interest, is the apparent hormesis induced at 0.0025pg/ml MNU. The principle adduct responsible for MNU mutagenesis is 0 6Methylguanine (06MeG) that miscodes during replication and becomes fixed as GC->AT transitions. Accordingly, the non-linear increase in mutant frequency is accompanied by a non-linear increase in GC->AT transitions. Furthermore, evidence is provided that implicates methlyguanine methyltransferase (MGMT) in protecting DNA from MNU induced mutagenesis by repairing 0 6MeG at low doses, thereby creating the NOGEL. AHH-1 cells treated with 0 6Benzylguanine (06BG), to inactivate MGMT, were hypersensitive to low dose MNU mutagenesis. At 0.0075pg/ml MNU, there was a three-fold increase in mutant frequency and an increase in proportion of GC-^AT transitions, from 28% to 48% in MGMT inactivated cells. This thesis presents a non-linear dose-response for MNU with a strong biological mechanism of action involving DNA repair.
published_date 2012-12-31T03:57:09Z
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