Genotoxicity and Mutagenicity Mechanisms and Test Methods

Book Chapter

Summary *

Organisms living in the real world are inevitably exposed to many chemical,physical, and biological agents that are harmful: food additives, natural toxins,pesticides, nanomaterials, metals, radiation, and viruses, among others. However,most of these agents, if not all, may have unexpected consequences on the biota.Organisms are continuously exposed to heterogeneous xenobiotics released intodifferent habitats either deliberately, inadvertently, or through non-regulatedindustrial discharges. Understanding how these agents can produce geneticalterations in DNA and what their role is in different biological systems continueto receive intense attention in fields such as health, pharmaceutical, environment,industry, agriculture, and food sectors.Mutagenicity denotes the generation of stable changes in the DNA moleculethat differ from the normal sequence of an organism, which may result in atransmissible change in the genotype of living organisms. Any damaged geneticmaterial could result in mutations, thus stimulating carcinogenic progressionor establishing a framework for hereditary disorders. Whereas mutations aregenerated mainly by exogenous agents, named mutagens, the term genotoxicdescribes the capability of those chemical, physical, and biological agents todirectly affect the structure of DNA, the cellular spindle apparatus, and/or thetopoisomerase enzymes that modulate DNA topology during DNA replication aswell as chromosome segregation, which are, finally, responsible for the fidelityof the genome. However, genotoxic damage to DNA is not always associated withmutations. Spontaneous mutations arise from a variety of sources due to errorsin DNA replication, repair, and recombination, and the presence of transposablegenetic elements. Many agents can produce chemically reactive species duringtheir metabolism, or are themselves reactive and may, therefore, cause irreversiblechanges to DNA.Heritable changes are the origin of innate metabolic deficiencies in cellularsystems, generating morbidity and mortality in organisms. Genetic disorders canbe produced by a mutation in only one or in multiple genes, through a combinationof gene mutations and environmental factors or by damage at the chromosomallevel that affects the number and/or structure of entire chromosome(s), or partsthereof. Mutations in cells are not only involved in the initiation and promotionof several human diseases, including cancer, but are also implicated in severalgenetic disorders, like anaemia, diabetes, cardiovascular alterations, obesity,atherosclerosis, and numerous other degenerative disorders. Currently, scientistsrecognize more than 4,000 human diseases that are produced by mutations as aresult of a combinatorial failure of more than one of these processes.As indicated in a book we published some years ago, entitled ?Genotoxicity-APredictable Risk To Our Actual World?, without knowledge of the mutagenic andgenotoxic properties of chemical, physical, and biological agents, the evaluationof responses in living organisms, including humans, is difficult, and consequentlythe regulation of genotoxicants is a complex and difficult process. Accurateidentification of the different classes of environmental genotoxicants and mutagensIVwould permit international regulatory scientific agencies to use this informationin a variety of legislative decisions to establish priorities of public and scientificconcern.We have attempted to compile information from different fields, highlighting thedetrimental influence that mutagenic and genotoxic agents inflict on DNA and howantimutagenic and anticarcinogenic modulators are able to reduce the negativeimpact of such toxic agents on living species. Antimutagens and anticarcinogensare agents that decrease the number of mutations in cells, modulating hostdefence mechanisms. Therefore, knowledge regarding the mechanism of action ofpotentially mutagenic and/or carcinogenic agents provides the basis for elucidationof how these protective chemicals exert a response. Antimutagens are employedas one of the key methods to increase cellular resistance to mutagens. They areable to reduce or even remove the mutagenic effects exerted by toxic xenobiotics,stimulating compensatory repair and tolerance pathways in the DNA. In regard totheir mode of action, antimutagens can act by influencing different targets, suchas cellular membranes, DNA damage repair, replication, chromatin organization,and cell signalling.This book opens with an interesting discussion about the use of yeast as a modelorganism for studying the biological effects of the P450-mediated metabolismof xenobiotics. This chapter also focuses on strategies for employing multiplegenetic endpoints in screening chemicals, yeast strains that facilitate phenotypingcytochrome P450 polymorphisms to test the safety of thousands of chemicals,the limitations of animal systems, the advantages of model organisms, andthe humanization of yeast cells by expressing human cytochrome P450 genes.The second chapter describes a possible molecular mechanism for how the additionof exogenous polyamines may increase the production of improved strainsof filamentous fungi and the biotechnological applications of this phenomenon.The third chapter provides information on chemical and physical mutagenesisin breeding, exemplified by new modern homozygous self-pollinated sunflowerlines, as well as additional recommendations on the use of methods to inducemutagenesis, including methods of generation, investigation, and subsequent use ofmutations. The fourth chapter comprises an excellent review comparing the specifictoxicity and genotoxicity exerted by heavy metals such as lead and cadmiumusing mammalian cells as a biological matrix in the context of ecotoxicology. Thefifth chapter describes the importance of doublecortin-like kinase 1 (DCLK1), amember of the protein kinase superfamily and the doublecortin family, and its rolein DNA damage response and repair, via direct and indirect mechanisms. It is wellknown that DCLK1 is expressed in cancer stem cells, and is implicated in initiatingtumours. The sixth chapter reviews the role of oxidative stress induced by vanadium(a common mechanism of action of metal pollutants), observed in in vivo and invitro systems, highlighting the way the production of free radicals inflicts damagein biomolecules including DNA, proteins, lipids, and carbohydrates. In addition,the chapter emphasizes the protective role of two water-soluble antioxidants,namely carnosine and ascorbate, present in biological systems. The seventh chapterconstitutes an update on how the w-/w+ somatic mutation and recombinationtest of Drosophila melanogaster are employed extensively for antigenotoxicityanalysis, focusing on actual published results to aid in the development of a reliableprotocol in antigenotoxicity. Finally, this book comprises a chapter discussing theproperties of antimutagenic substances with multiple mechanisms of action, inaddition to introducing different aspects of natural and synthetic antimutagens.XIVVFurther, the chapter includes a brief compilation of scientific findings, either fromdietary sources or synthetic agents, with potential to combat the disorders causedby the mutagenic agents, noting possible future perspectives and mechanisms ofantimutagenics.The editors of Genotoxicity and Mutagenicity - Mechanisms and Test Methodsare enormously grateful to all contributing authors for sharing their knowledge andinsights in this book. They have made an extensive effort to gather the informationincluded in every chapter. Readers are challenged to interpret the significance ofvarious mechanisms and tested methodologies for detecting the causes and consequencesof mutagenic and genotoxic agents. We hope that the topics discussed hereencourage all those interested to explore new aspects of the fields of mutagenesisand genotoxicity by stimulating scientific dialogue. The publication of this bookis of great importance to scientists, biologists, pharmacologists, physicians, andveterinarians, as well as engineers, teachers, graduate students, and administratorsof environmental programmes, who can make use of these investigations tounderstand some aspects of mutagenic and genotoxic issues, making this volume avaluable reference in the future. Information provided by the agent in SIGEVA