DDT 4 - Mutagens Flashcards
Toxicants
Any substance (poison) that causes harm to a living organism
- Distributed - Metabolized - Interact with cellular macromolecules - result in toxic endpoint - excretion and repair process can mitigate toxin effects
Toxicology
Study of toxicants (chemical/physical)
Include areas of:
- analytical toxicology (identifying toxicants and metabolites)
- toxicity testing (living systems to estimate toxicity effects, simple cell culture techniques)
- toxicologic pathology (investigates subcellular/cellular/tissue/organ changes due to toxicants)
- structure activity studies (identifies relationships between structure and toxic effects to predict toxicity)
- statistics and epidemiology (determine significance and risk associated with toxicant exposure within human populations)
Sir Percivall Pott (1776)
Reported chimney sweeps had a higher incidence of scrotal cancer
Attributed it to increase topical exposure to soot and tar
K. Yamagiwa, K. J. Itchikawa (1915-18)
Demonstrated multiple applications of coal tar to rabbit skin produced carcinoma
First demonstration that chemical could produce cancers in animals
Established link between epidemiology studies and animal carcinogenicity
Mutagens
Chemical/physical phenomenon (radiation) that can cause changes to the composition of DNA
Increase the rate of mutations in DNA compared to spontaneous mutation rate
Mutations can lead to development of cancer
Many mutagens are also carcinogens
Physical Mutagens
EM radiation
– UV light
(ionizing radiation, dimerization of pyrimidine, hydration of cytosine, indirectly damages DNA by production of reactive oxygen species)
– X-rays / Gamma rays
(shorter wavelength, travels through cell without collision, if collides with DNA, strand break)
Particle Radiation
– Alpha/Beta particles (upon impact with nuclear DNA, attract/repel charged areas of DNA, breaking DNA)
Chemical Mutagens
Testing for Potential Chemical Mutagens/Carcinogens
Ames Test (UC 1970s)
Montiors chemicals ability to bring about reverse mutation in Salmonella typhimurium strains that have defects in their histidine synthesis pathway
Strains do not grow in absence of histidine
Cells can mutate back to wild type and grow in absence of histidine
If no histidine, bacteria will not grow and will not form colonies
But cells can mutate back to wild type - reactivation of enzyme responsible of histidine synthesis in bacteria
Salmonella bacteria will be able to grow in absence of histidine in growth media
Ames Test
- Chemical (suspected carcinogen) and suspension of cells containing His- (strain which cannot synthesize histidine)
- Incubated with rat liver enzymes to produce activated electrophilic species (simulate metabolic activation for these suspected carcinogens in the body)
- Bacterial test culture plated onto agar plate with *no histidine
- Presence of colonies indicates some cells have reverted to wild type (positive result)
- Positive result in Ames test shows compound is a conformed mutagen
- Different strains can indicate particular types of mutations (base pair, frame shift)
- For validity, +/- controls and varying concentration of chemical are used in test
Carcinogenesis
Process through which cancer develops
- Chemical carcinogenesis = study of chemical carcinogens and mode of action
Chemical Carcinogens
Change composition of DNA, cause cancer
Tumor Suppressor Genes
Negative regulators of cell growth
Inactivated in cancer cells
Proto-oncogenes
Found in normal cells
involved in positive regulation of cell growth
mutated in cancer cells
Pre-neoplastic region
High probability of progressing into a malignant tumor
Carcinogenesis: Initiation to Progression
= Conversion
transformation of preneoplastic cell into one that expresses malignant phenotype
exposure to UV light can accelerate
= Progression
expression of malignant phenotype
cells acquire aggressive characteristics (genomic instability, uncontrolled growth, metastasis)