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Testing the Mutagenicity Potential of Chemicals Geert R Verheyen*, Koen Van Deun and Sabine Van Miert

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Testing the Mutagenicity Potential of Chemicals Geert R Verheyen*, Koen Van Deun and Sabine Van Miert ISSN: 2378-3648 Verheyen et al. J Genet Genome Res 2017, 4:029 DOI: 10.23937/2378-3648/1410029 Volume 4 | Issue 1 Journal of Open Access Genetics and Genome Research ORIGINAL RESEARCH Testing the Mutagenicity Potential of Chemicals Geert R Verheyen*, Koen Van Deun and Sabine Van Miert Thomas More University College, Belgium *Corresponding author: Geert R Verheyen, Radius, Thomas More University College Campus Geel, Kleinhoefstraat 4, 2440 Geel, Belgium, Tel: +32-0-14-562310, E-mail: [email protected] Abstract fully replicated DNA molecules to the 2 daughter cells occurs accurately. However, DNA replication is not a All information for the proper development, functioning faultless process and mutations, which can be defined and reproduction of organisms is coded in the sequence of matched base-pairs of DNA. DNA mutations can result as various types of permanent changes in DNA, do oc- in harmful effects and play a role in genetic disorders and cur in all organisms. Mechanisms underlying mutations cancer. As mutations can arise through exposure to chem- have been well studied and are described in many text- ical substances, testing needs to be done on substances books [1]. Whether mutations will affect gene function that humans and animals can be exposed to. This review depends on where they occur within a gene or whether focuses on the different testing strategies for risk assess- ment of chemicals for genotoxicity and carcinogenicity. This they affect levels of gene expression, mRNA splicing or review is not meant to cover all testing methodologies, but protein composition. About 70% of the mutations that rather to give an overview of the main methodologies that result in an amino acid change in a protein is estimated are used in a regulatory context. In silico and in vitro tools to be harmful [2]. are playing an increasingly important role, in order to reduce in vivo animal testing. Especially in silico tools like (Q)SARs A first type of mutation occurs due to the incorpo- are promising as they are non-testing methods and thereby ration of a wrong base during replication. This can oc- also reduce the costs and time that are needed to perform cur spontaneously or can be chemically induced and in vitro assays. (Q)SARs are not sufficiently reliable to be used as stand-alone tools, and should be associated with will result in a mismatch between base pairs. If this is expert judgment or used in combination with other Weight of not repaired, it will lead to a mutation in the next round Evidence such as in vitro and in vivo data and data derived of replication. Misincorporations lead to transitions in from other similar molecules (read-across). For some prod- which a pyrimidine is changed into the other pyrimidine uct (sub) categories, testing (in vitro/in vivo) will be unavoid- able; however the future may bring reliable approaches for or a purine into the other purine and to transversions ensuring human safety. in which a pyrimidine is changed into a purine or vice versa. Keywords Mutagenicity, In vivo, In vitro, QSAR, Hazard identification, Risk Other types of mutations include insertions or dele- assessment tions of 1 or more base pairs into the DNA sequence. Mutations can also involve amplifications or deletions Introduction of large chromosomal areas leading to multiple copies or loss of the genes located within this region, respec- The genetic make-up of all organisms is contained tively [3]. These complex mutations are caused by chro- within the double helix of DNA. All information for the mosomal translocations, interstitial deletions and chro- development, functioning and reproduction of organ- mosomal inversions and can also result in juxtaposition isms is coded within the sequence of matched base-pairs of previously separate pieces of DNA, potentially even and it is of crucial importance that this information is forming functionally distinct fusion genes, with poten- passed on to progeny without or with the least amount tial harmful effect. of error possible. Thus at the cellular level it is important that the replication of DNA and the segregation of the Finally, during mitosis or meiosis, large chromosomal Citation: Verheyen GR, Deun KV, Miert SV (2017) Testing the Mutagenicity Potential of Chemicals. J Genet Genome Res 3:029. doi.org/10.23937/2378-3648/1410029 Received: June 18, 2016: Accepted: May 13, 2017: Published: May 15, 2017 Copyright: © 2017 Verheyen GR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Verheyen et al. J Genet Genome Res 2017, 4:029 • Page 1 of 11 • DOI: 10.23937/2378-3648/1410029 ISSN: 2378-3648 pieces or even whole chromosomes may be lost during ity of chromosomal abnormalities result from trisomies the formation of daughter cells due to missegregation and occur prenatally [11]. As exposure of the develop- events or chromosome breakage. This may also result ing infants to specific chemicals has been shown to in- in the loss or increase in number of alleles of genes, duce birth defects, it is important to sufficiently screens with deleterious effects for the organism. These types new compounds for potential teratogenic effects prior of genotoxicants are non-mutagenic and they may to release to the market [12]. have threshold mechanisms. Typical examples are topi- The correlation between the mutagenicity and car- somerase II poisons or mechanisms based on reactive cinogenicity of chemicals has long been evident [13]. oxygen species; other mechanisms may lead to aneu- Another demonstration of this association is presented ploidy [4-6]. by the correlation of human chromosome instability DNA damage introduced by endogenous and ex- syndromes and DNA repair deficiencies, with increased ogenous sources continuously threatens the structure cancer risks [14]. Molecular studies of so-called pro- and integrity of DNA molecules. Due to the deleterious to-oncogenes and tumor suppressor genes have also effects that mutations can have on the functioning of shown that mutations play an important role in the gene products, organisms have evolved complex DNA processes leading to cancer. These genes encode for repair mechanisms that are aimed to prevent or correct proteins that typically help to control cell growth and mutations by reverting the mutated sequence back to proliferation. Proto-oncogenes (e.g. ras) can be con- its original state before they are fixed as permanent ge- verted into active oncogenes by point mutations [15] or netic changes [7]. If DNA lesions remain unrepaired or chromosomal aberrations, and subsequently stimulate if they are erroneously repaired, they will most proba- the transformation of normal cells into cancer cells [16]. bly hamper crucial cellular processes like transcription A tumor suppressor gene (e.g. p53) typically protects a and replication, which may result in cell cycle arrest and cell by inhibiting cell proliferation and tumor develop- possibly (programmed) cell death. However, potentially ment, and mutational inactivation or deletion of these the mutation may become fixed. At the level of the or- genes have been implicated in human tumors [17]. ganism, mutations in germ cells can result in genetically Many cancers involve both activation of oncogenes and inherited diseases, while accumulation of mutations in inactivation of tumor suppressor genes, as well as oth- somatic cells is associated with the initiation and pro- er possible events. This implies that carcinogenesis is a gression of cancer. DNA damage is also believed to be multistep process resulting from an accumulation of- ge involved in aging [8]. netic alterations [18-20]. Mutations and Pathogenesis Hazard assessment for genetic toxicity is done by means of testing and non-testing methods as will be In this short overview paper we focus on the implica- discussed in this overview. Also available human data is tions of mutations for humans. The importance of DNA important for hazard assessment. This is closely related and the impact of mutations and chromosomal aberra- to the hazard assessment for carcinogenicity, at least tions for human health are clear from their observed for genotoxic carcinogens. roles in numerous genetic diseases and cancer. There- fore potential for mutations in both somatic and germs Non-genotoxic carcinogens, will not be positive in cells need to be taken into account when an overall risk genotoxicity studies because they act via other mecha- estimate resulting from mutations is concerned [9]. nisms (e.g. peroxisome proliferator-induced hepatocar- cinogenesis in rodents; [21] and thus need other testing Many genetic disorders (e.g. cystic fibrosis) are re- methods. However this is out of scope of this review. cessive in nature, indicating that the underlying muta- tions are expressed when an affected individual inherits Risk assessment for genotoxicity is not as easily per- the mutated gene from both parents. Disorders show- formed as for carcinogenicity. The usual approach is to ing a dominant inheritance pattern require only 1 copy combine rodent germ and somatic cell data for induced of the mutated gene in order to become expressed in genetic alterations with human somatic cell data (if the affected individual. For dominant genetic disorders available) in order to estimate the frequency of muta- a single mutation is sufficient for disease expression, tions in human cells. For a complete estimate of genetic risk, it is then necessary to obtain an estimate of the and therefore new mutations make a larger contribu- frequency of genetic alterations that are transmitted to tion to the incidence of dominant diseases [9]. Howev- the offspring [22]. er, the occurrence of a mutation can be obscured by in- complete penetrance of the affected phenotype. Chemical Mutagens and Classification Structural chromosome aberrations can cause mis- Reactive chemicals that can induce covalent bond carriage and fetal death or serious abnormalities [10].
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