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ch 9 toxicology
| Question | Answer |
|---|---|
| Six acquired characteristics essential for tumor formation | Self-sufficiency in growth signals 2.Insensitivity to antigrowth signals 3.Evasion of apoptosis 4.Limitless replicative potential 5.Sustained angiogenesis Tissue invasion & metastasis |
| Cancer Risk Assessment | .Investigate sensitivity of different species & subpopulations to tumor induction by a chemical 2.Develop dose-response curve of mutations caused by the chemical |
| Genetic Risk Assessment | 1.Extrapolate frequency of genetic alteration in human germ cells from data of rodent germ cells & somatic cells 2.Complete assessment requires estimation of genetic alteration frequency transmitted to offspring |
| DNA Damage | 1.Single- or double-strand breaks 2.Cross-links between bases or between bases & proteins 3.Chemical adducts (additions) to bases 4.Apurinic/apyrimidinic sites Alkylation via addition or substitution |
| DNA Repair- 2 processes | 1.Less severe damage, repair processes return DNA to undamaged state (error-free) or to improved but still altered state Extensive damage, apoptosis |
| .Ionizing Radiations | X-rays, γ-rays, α particles - produce DNA single- & double-strand breaks, base damage |
| .Ultraviolet Light | nonionizing radiation - 2 predominant lesions: dimerization of 2 adjacent pyrimidine bases & photoproducts |
| Chemicals | produce changes directly (DNA-reactive) as adducts or indirectly by chemical insertions between base pairs, base losses (AP or abasic site), insertion of incorrect bases into AP sites, interference with polymerases |
| .Endogenous Agents | cause several 100 DNA damages/cell/day = altered DNA bases, AP sites, formation of reactive oxygen species (ROS), deamination processes |
| DNA replication | error-prone: addition of incorrect bases |
| DNA Repair | basic principles: 1) damage recognition, 2) direct reversal or removal of damage, 3) repair of DNA synthesis, 4) ligation |
| .Base excision repair | removal & replacement of damaged base |
| .Nucleotide excision repair | removal & replacement of bulky lesions |
| Homologous recombination | production of 3′-ended single-stranded tail which invades an undamaged homologous DNA molecule + DNA synthesis, forms a Holliday junction DNA complex. Cleavage of Holliday junction produces two undamaged DNA molecules |
| .Nonhomologous end-joining | produces double-strand breaks, followed by recombination & religation of DNA pieces |
| Mismatch repair | damage recognition by protein that binds to mismatch, stabilization of binding by addition of >1 proteins, cut DNA at distance from mismatch, excision past mismatch, resynthesis, ligation |
| O6-methylguanine-DNA methyltransferase (MGMT) repair | MGMT transfers methyl group from DNA O6-methylguanine to a cysteine residue; adducted base is reverted to normal MGMT |
| Somatic cells | mis-repair in G1 & G2, replication errors during S phase 1.Structural chromosome aberrations - chromosomal exchanges, terminal deletions |
| Formation of Gene Mutations •Somatic cells | race between repair & replication 1.Base substitutions including transitions, transversions 2.Frameshift mutations 3.Deletions |
| Cell-cycle checkpoint genes | role in initiating repairs before cell enters S phase |
| Germ cells | Spermatogonial stem cells: *major contributor; oocytes: resistant due to arrest in meiosis I |
| Ionizing radiations cause | DNA repair errors; nonradiomimetic chemicals cause DNA replication errors |
| Numerical chromosome changes | chromosome segregation errors (nondisjunction) |
| Sister chromatid exchange | S phase replication errors |
| Germ cells | .Same as somatic cells 2.Chromosome segregation during meiosis aberration recovery probability |
| Genetic toxicology assays | :2 interrelated but distinct purposes 1.Identifying mutagens for hazard identification 2.Characterizing dose-response relationships & mutagenic mechanisms |
| Prediction of genotoxicity | 1.Interpretation of chemical structure 2.In silico predictive computer models |
| DNA damage and repair assays | 1.Direct detection of DNA damage 2.DNA repair, recombination, genotoxic stress responses as indicators of damage |
| Prokaryote gene mutation assays | 1.Bacteria forward mutation assays 2.Bacteria reverse mutation assays* |
| Assays in nonmammalian eukaryotes | 1.Fungal assays 2.Plant assays 3.Drosophila assays |
| Mammalian gene mutation assays | 1.Forward mutation in vitro assays 2.Somatic cell gene mutation in vivo assays 3.Transgenic assays |
| Genetic toxicology assays: 2 interrelated but distinct purposes | 1.Identifying mutagens for hazard identification 2.Characterizing dose-response relationships & mutagenic mechanisms |
Created by:
aceofspades08