Molecular dosimetry of chemical mutagens. Relationship between DNA adduct formation and genetic changes analyzed at the molecular level. 1996

A A van Zeeland
MGC-Department of Radiation Genetics and Chemical Mutagenesis, State University of Leiden, The Netherlands.

This is a review of the work carried out by 16 collaborating institutes within a project which was part of the European Programme: Science and Technology for Environmental Protection (STEP). The purpose of the project was to investigate the relationship between the exposure to genotoxic chemicals and the induction of DNA damage and genetic effects as determined in in vitro and in vivo assays under laboratory conditions. Two types of investigation were performed: (i) determination of the relationship between the extent of exposure to a genotoxic chemical and the frequency of DNA adducts formed in the test organism and (ii) identification of those DNA adducts which are responsible for the biological effects of genotoxic chemicals. The research was carried out with a series of alkylating agents which all induce similar types of DNA damage but for which the proportions of the different types of adducts vary. The frequency of this type of DNA damage was also modulated by base excision repair processes. In addition, a number of genotoxic agents which cause DNA damage recognized by nucleotide excision repair were investigated. The consequences of DNA adduct formation, i.e., the induction of gene mutations, were analyzed at the DNA sequence level, generating mutational spectra. These investigations of the mutational specificities of carcinogens contributed to our understanding of the molecular mechanisms which are involved in cancer induction by genotoxins.

UI MeSH Term Description Entries
D009153 Mutagens Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. Clastogen,Clastogens,Genotoxin,Genotoxins,Mutagen
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004260 DNA Repair The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones. DNA Damage Response
D006147 Guanine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000478 Alkylation The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. Alkylations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

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