Download Genetic Toxicology

Genetic Toxicology
• Mutation - a heritable change produced in
the cell genotype.
• Effects Produced by Genetic Toxins
– Aneuploidization
– Clastogenesis
– Mutagenesis
• Somatic vs. Germ Cell Mutations
Consequences of Point Mutations
• Base Pair Transitions
– A:T
– T:A
G:C or G:C
C:G or C:G
A:T (Purine
T:A (Pyrm
Purine)
Pyrm)
• Base Pair Transversions
– A:T
– G:C
T:A or C:G
T:A or C:G
• Base Pair Addition or Deletion
– Frame shift mutation
Mechanisms of Point Mutation
• Base-pair Transformations and Substitutions
– Deamination of Adenine and Cytosine by Nitrous
Acid
– Alkylation at O6 and N7 of Guanine by
alkylnitrosamine
Mechanisms of Point Mutation
• Base-pair Transformations and Substitutions
– Alkylation - N1 of Adenine; N3 of Cytosine by
Vinyl chloride
• A:T
C:G Transversion
– 5-BromoUracil
• A:T
G:C Transitions
• Framshifts
– Intercalation of planar molecules – Acridine
orange
Chromosome Breakage/Deletion
• Clastogenesis – Clastogens
– Alkylating agents
– Agents that interfere with normal repair
processes, i.e. cut & patch repair, SCE
– Chromatid & Chromosome breaks
• Chromosomal Aberrations
– Inversions, Deletions, Acentric fragments,
Dicentrics, Ring chromosomes
Aneuploidy/Polyploidy
• Metaphase poisoning – interfering with the
processes of mitosis and meiosis
–
–
–
–
Positioning of centrioles
Arrangement of chromosomes at metaphase
Spindle fiber formation
Partitioning of chromosomes
Coping With DNA Damage?
• Damage Tolerance
– Replication by passes damaged site – Recombinational
repair?
• DNA Repair Mechanisms
– Direct Reversal
– Excision Repair
• Nucleotide excision
• Base excision
– Recombinatorial Repair
Genotoxicity Assays
• Assays for gene mutations
– Bacterial reverse mutation assays (Ames test)
– TK or HPRT forward mutation assays in cultured
mammalian cells
• Cytogenetic analysis – mammalian cells
– DNA damage – Comet assay
– Chromosomal aberrations & micronuclei
– Sister Chromatid Exchange & Aneuploidy
• Mammalian germ-cell assay
– Specific locus test – recessive mutations
– Dominant lethal mutations