The Influence of Oxidative Stress, Carcinogens and Cloning on DNA ...

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Introduction 1.2.8 Twins <strong>and</strong> epigenetics overview Monozygotic (MZ) twins originate from the same zygote <strong>and</strong> split into two eggs in the gestational period <strong>and</strong> are supposed to share identical epigenomes when the blastocyst splits. Studies had concluded that the time frame <strong>of</strong> splitting plays a role whether identical twins or conjoined twins (splitting after 12 days) are conceived. Surely, dizygotic (DZ) twins developed from different zygotes carrying different epigenetic pr<strong>of</strong>iles. It was observed that MZ twins could show varying behaviour in the incidence <strong>of</strong> psychiatric diseases such as schizophrenia <strong>and</strong> bipolar disorders as well as other diseases like Parkinson’s <strong>and</strong> cancer (147-150) . This differential susceptibility to the diseases was returned to the role <strong>of</strong> the environmental agents in affecting the epigenome (151) <strong>and</strong> then the twins manifest a difference in phenotype. However, the accumulating evidence (152, 153) had recently highlighted that the change in DNA methylation <strong>and</strong> chromatin structure <strong>of</strong> mammalian genome induced due to exposure to the environment significantly alters the gene function associated with different phenotypic outcomes (149, 154) . Additionally, Kaminsky et al. (155) had proved that the epigenetic pr<strong>of</strong>iles are not fully determined by DNA sequence, otherwise MZ twins should not show epigenetic differences. Most MZ twins showed the same methylation status, whereas few others showed aberrant methylation pr<strong>of</strong>iles. This epigenetic variation between twins explain the etiology <strong>of</strong> the complicated diseases developed by one <strong>of</strong> the traits (149) . <strong>The</strong> correlation between the diversion <strong>of</strong> the epigenetic pr<strong>of</strong>ile in the late adolescent <strong>and</strong> the development <strong>of</strong> the disease despite the same epigenetic status after twin separation is cleared by epigenetic model <strong>of</strong> twin discordance for psychosis represented by Petronis et al. (147) . In conclusion, the DNA methylation, this dynamic process throughout the life time, affects the gene expression by shutting some genes <strong>of</strong>f or increasing the role <strong>of</strong> others. <strong>The</strong> accumulation <strong>of</strong> these variations <strong>of</strong> gene expression in MZ twins contributes to their discordance <strong>and</strong> their response to the diseases. Additionally, in the recent years there is doubt concerning the assumption that MZ twins are genetically identical organisms due to findings <strong>of</strong> the researchers about the change on the genetic level associated with the gene sequence. This issue is still under investigation. 14
1.3 DNA adducts 1.3.1 DNA adducts <strong>and</strong> cancer 15 Introduction <strong>The</strong> formation <strong>of</strong> DNA adducts is resulted from the covalent interaction <strong>of</strong> genotoxic carcinogens with DNA, derived from exogenous <strong>and</strong> endogenous sources, either directly or following metabolic activation (156, 157) . If this DNA modification is not repaired, it will lead to mutations in critical genes such as those involved in the regulation <strong>of</strong> cellular growth <strong>and</strong> subsequently to cancer development ( 158) (Fig. 7). Excretion Normal DNA Apoptosis DNA Repair Endogenous& Endogenous& Exogenous source <strong>Carcinogens</strong> Metabolic detoxification Metabolic activation DNA adducts Figure 7: <strong>The</strong> pathway <strong>of</strong> DNA adducts formation DNA Replication Alteration <strong>of</strong> tumor suppressor genes Mutation Cancer As shown by the Salmonella test established by Ames (159) <strong>and</strong> by other tests (160-162) , most carcinogens are either mutagens (electrophilic reactants that covalently bind to DNA bases) or premutagens (chemicals that undergo metabolic conversion to such electrophilic compounds). However, the majority <strong>of</strong> the genotoxic carcinogens require metabolic activation in order to form electrophilic reactive species that bind covalently to nucleophilic sites in DNA (161) . Generally speaking, nitrogen <strong>and</strong> oxygen centres are the prefered nucleophilic sites on DNA to be attacked by alkylating <strong>and</strong> arylating agents (163) . DNA damage is induced either by normal cellular processes or by some environmental agents. Either endogenous or exogenous mediated-DNA damage share similarities in occurrence as well as in cell response. <strong>The</strong> damage is occurred initially either by involvement <strong>of</strong> free radicals (ionizing radiation, UV light, oxidative stress) or adduct formation (mutagenic
Page 1 and 2: The Influe
Page 3 and 4: The work at h<stro
Page 5 and 6: First, I feel always grateful to Al
Page 7: I would like to extend my thanks to
Page 11 and 12: The following acro
Page 13 and 14: FDA Food and drug
Page 15: RIA Radioimmunoassay ROS Reactive o
Page 18 and 19: Index 3.1 Spectrophotometeric deter
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Page 22 and 23: Introduction 1.1.2 DNA methylation
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Page 26 and 27: Introduction Figure 4: Model for me
Page 28 and 29: Introduction Cancer is classified i
Page 30 and 31: Introduction DNA methylation Gene h
Page 32 and 33: Introduction 1.2.7.1 Clonin
Page 36 and 37: Introduction chemicals, alkylating
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Page 42 and 43: Introduction Finally, flavo- <stron
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Page 58 and 59: Introduction - Radioactive-mediated
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Summary 4 Summary DNA methylation i
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Summary The same s
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Experimental part Sodium tetrapheny
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Experimental part � Sodium tetrab
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Experimental part framework was fas
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Experimental part propanol
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Experimental part 12.5 mU/µL SPD)
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Experimental part Condition Value D
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Experimental part 5.4 Instrumentati
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Experimental part Graduated cylinde
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Experimental part 3-Nitrobenzanthro
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Appendix In-vitro: Denoting a react
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Appendix Laboratory Document Hydrol
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Appendix BODIPY and</strong
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Appendix Description of</st
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Appendix Transmission [%] 120 100 8
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Appendix Figure 62: Mass spectrum E
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List of figures Fi
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List of tables 8 L
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Literature Literature 1. Egger, G.;
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Literature 41. Bestor, T.H.; "<stro
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Literature 78. Venitt, S.; "Mechani
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Literature 113. Sinclair, K.D.; Mce
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Literature 148. Kadan-Lottick, N.S.
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Literature cyte DNA by gas chromato
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Literature 221. Mirand</str
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Literature 257. Lingaraju, G.M.; Sa
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Literature different tissues <stron
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Literature 324. Vishwanath, B.S.; F
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Literature 359. Wei, L.; Li, R.K.;
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Literature 394. Ramsahoye, B.H.; "M
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Literature 431. Wirtz, M.; Schumann
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Literature 467. Cornelius, M.; Wort
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Literature 502. Issa, J.P.J.; Ottav
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Literature 536. Pinheiro, J. <stron
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