Physiologically based in silico modelling to examine DNA adduct formation by different food-borne a,ß-unsaturated aldehydes at realistic low dietary exposure levels

R. Kiwamoto

Research output: Thesisinternal PhD, WUAcademic

Abstract

Abstract (R.Kiwamoto ISBN 978-94-6257-284-3)

Various α,β-unsaturated aldehydes are present in fruits, vegetables, spices, or processed products containing these items as natural constituents or as added food flavouring agents. Because of the α,β-unsaturated aldehyde moiety the β carbon in the molecule becomes electron deficient and the aldehydes react with electron rich molecules including DNA via Michael addition. The formation of DNA adducts raises a concern for genotoxicity, although formation of DNA adducts may not be significant at low doses relevant for dietary exposure in vivo because of adequate detoxification. This thesis therefore aimed at determining dose-dependent detoxification and DNA adduct formation of food-borne α,β-unsaturated aldehydes by using a physiologically based in silico modelling approach in order to contribute to the safety assessment of these aldehydes used as food flavourings instead of performing animal experiments.

Physiologically based in silico models were developed for 18 α,β-unsaturated aldehydes. The model outcomes indicated that the DNA adduct formation by the 18 α,β-unsaturated aldehydes as food flavourings is negligible and does not raise a safety concern at their levels of intake resulting from their use as food flavourings. The application of QSAR models strongly accelerated the development process of the PBK/D models of the group of 18 compounds. Also, it was illustrated that physiologically based in silico models provide a very useful and powerful tool to facilitate a group evaluation and read-across for food-borne DNA reactive agents. PBK/D models developed for the group of compounds supported read-across from cinnamaldehyde which is known not to be genotoxic or carcinogenic in vivo to other aldehydes, by allowing comparison of dose-dependent DNA adduct formations. Altogether this thesis presented physiologically based in silico modelling as an approach to test relevance of positive in vitro genotoxicity results by DNA reactive compounds in vivo without using animal experiments.

 

 

 

LanguageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
Supervisors/Advisors
  • Rietjens, Ivonne, Promotor
  • Punt, Ans, Co-promotor
Award date13 May 2015
Place of PublicationWageningen
Publisher
Print ISBNs9789462572843
Publication statusPublished - 2015

Fingerprint

DNA Adducts
Aldehydes
Detoxification
DNA
Animals
Molecules
Electrons
Vegetables
Fruits
Carbon
Experiments

Keywords

  • aldehydes
  • dna
  • detoxification
  • food additives
  • flavourings
  • genotoxicity
  • carcinogens
  • models
  • mathematical models
  • physiology
  • simulation models
  • toxicology

Cite this

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title = "Physiologically based in silico modelling to examine DNA adduct formation by different food-borne a,{\ss}-unsaturated aldehydes at realistic low dietary exposure levels",
abstract = "Abstract (R.Kiwamoto ISBN 978-94-6257-284-3) Various α,β-unsaturated aldehydes are present in fruits, vegetables, spices, or processed products containing these items as natural constituents or as added food flavouring agents. Because of the α,β-unsaturated aldehyde moiety the β carbon in the molecule becomes electron deficient and the aldehydes react with electron rich molecules including DNA via Michael addition. The formation of DNA adducts raises a concern for genotoxicity, although formation of DNA adducts may not be significant at low doses relevant for dietary exposure in vivo because of adequate detoxification. This thesis therefore aimed at determining dose-dependent detoxification and DNA adduct formation of food-borne α,β-unsaturated aldehydes by using a physiologically based in silico modelling approach in order to contribute to the safety assessment of these aldehydes used as food flavourings instead of performing animal experiments. Physiologically based in silico models were developed for 18 α,β-unsaturated aldehydes. The model outcomes indicated that the DNA adduct formation by the 18 α,β-unsaturated aldehydes as food flavourings is negligible and does not raise a safety concern at their levels of intake resulting from their use as food flavourings. The application of QSAR models strongly accelerated the development process of the PBK/D models of the group of 18 compounds. Also, it was illustrated that physiologically based in silico models provide a very useful and powerful tool to facilitate a group evaluation and read-across for food-borne DNA reactive agents. PBK/D models developed for the group of compounds supported read-across from cinnamaldehyde which is known not to be genotoxic or carcinogenic in vivo to other aldehydes, by allowing comparison of dose-dependent DNA adduct formations. Altogether this thesis presented physiologically based in silico modelling as an approach to test relevance of positive in vitro genotoxicity results by DNA reactive compounds in vivo without using animal experiments.      ",
keywords = "aldehyden, dna, ontgifting, voedseladditieven, aromatische stoffen, genotoxiciteit, carcinogenen, modellen, wiskundige modellen, fysiologie, simulatiemodellen, toxicologie, aldehydes, dna, detoxification, food additives, flavourings, genotoxicity, carcinogens, models, mathematical models, physiology, simulation models, toxicology",
author = "R. Kiwamoto",
note = "WU thesis, no. 6025",
year = "2015",
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Physiologically based in silico modelling to examine DNA adduct formation by different food-borne a,ß-unsaturated aldehydes at realistic low dietary exposure levels. / Kiwamoto, R.

Wageningen : Wageningen University, 2015. 200 p.

Research output: Thesisinternal PhD, WUAcademic

TY - THES

T1 - Physiologically based in silico modelling to examine DNA adduct formation by different food-borne a,ß-unsaturated aldehydes at realistic low dietary exposure levels

AU - Kiwamoto, R.

N1 - WU thesis, no. 6025

PY - 2015

Y1 - 2015

N2 - Abstract (R.Kiwamoto ISBN 978-94-6257-284-3) Various α,β-unsaturated aldehydes are present in fruits, vegetables, spices, or processed products containing these items as natural constituents or as added food flavouring agents. Because of the α,β-unsaturated aldehyde moiety the β carbon in the molecule becomes electron deficient and the aldehydes react with electron rich molecules including DNA via Michael addition. The formation of DNA adducts raises a concern for genotoxicity, although formation of DNA adducts may not be significant at low doses relevant for dietary exposure in vivo because of adequate detoxification. This thesis therefore aimed at determining dose-dependent detoxification and DNA adduct formation of food-borne α,β-unsaturated aldehydes by using a physiologically based in silico modelling approach in order to contribute to the safety assessment of these aldehydes used as food flavourings instead of performing animal experiments. Physiologically based in silico models were developed for 18 α,β-unsaturated aldehydes. The model outcomes indicated that the DNA adduct formation by the 18 α,β-unsaturated aldehydes as food flavourings is negligible and does not raise a safety concern at their levels of intake resulting from their use as food flavourings. The application of QSAR models strongly accelerated the development process of the PBK/D models of the group of 18 compounds. Also, it was illustrated that physiologically based in silico models provide a very useful and powerful tool to facilitate a group evaluation and read-across for food-borne DNA reactive agents. PBK/D models developed for the group of compounds supported read-across from cinnamaldehyde which is known not to be genotoxic or carcinogenic in vivo to other aldehydes, by allowing comparison of dose-dependent DNA adduct formations. Altogether this thesis presented physiologically based in silico modelling as an approach to test relevance of positive in vitro genotoxicity results by DNA reactive compounds in vivo without using animal experiments.      

AB - Abstract (R.Kiwamoto ISBN 978-94-6257-284-3) Various α,β-unsaturated aldehydes are present in fruits, vegetables, spices, or processed products containing these items as natural constituents or as added food flavouring agents. Because of the α,β-unsaturated aldehyde moiety the β carbon in the molecule becomes electron deficient and the aldehydes react with electron rich molecules including DNA via Michael addition. The formation of DNA adducts raises a concern for genotoxicity, although formation of DNA adducts may not be significant at low doses relevant for dietary exposure in vivo because of adequate detoxification. This thesis therefore aimed at determining dose-dependent detoxification and DNA adduct formation of food-borne α,β-unsaturated aldehydes by using a physiologically based in silico modelling approach in order to contribute to the safety assessment of these aldehydes used as food flavourings instead of performing animal experiments. Physiologically based in silico models were developed for 18 α,β-unsaturated aldehydes. The model outcomes indicated that the DNA adduct formation by the 18 α,β-unsaturated aldehydes as food flavourings is negligible and does not raise a safety concern at their levels of intake resulting from their use as food flavourings. The application of QSAR models strongly accelerated the development process of the PBK/D models of the group of 18 compounds. Also, it was illustrated that physiologically based in silico models provide a very useful and powerful tool to facilitate a group evaluation and read-across for food-borne DNA reactive agents. PBK/D models developed for the group of compounds supported read-across from cinnamaldehyde which is known not to be genotoxic or carcinogenic in vivo to other aldehydes, by allowing comparison of dose-dependent DNA adduct formations. Altogether this thesis presented physiologically based in silico modelling as an approach to test relevance of positive in vitro genotoxicity results by DNA reactive compounds in vivo without using animal experiments.      

KW - aldehyden

KW - dna

KW - ontgifting

KW - voedseladditieven

KW - aromatische stoffen

KW - genotoxiciteit

KW - carcinogenen

KW - modellen

KW - wiskundige modellen

KW - fysiologie

KW - simulatiemodellen

KW - toxicologie

KW - aldehydes

KW - dna

KW - detoxification

KW - food additives

KW - flavourings

KW - genotoxicity

KW - carcinogens

KW - models

KW - mathematical models

KW - physiology

KW - simulation models

KW - toxicology

M3 - internal PhD, WU

SN - 9789462572843

PB - Wageningen University

CY - Wageningen

ER -