Toxicology - CH 08 Chemical Carcinogenesis
In the scenario of non-genotoxic (epigenetic) carcinogens, tumor formation can result via
*DNA methylation *Oxidative stress Cytotoxicity Receptor-mediated pathways Hormonal mode of action
Receptor-mediated
-P450 CYP inducers, cell proliferation and inhibits apoptosis -Peroxisome proliferator-activated receptor, bind to nuclear hormone receptor PPAR alpha, acts as transcription factor, and increases peroxisome volume in the cytoplasm
What are the possible fates of a cell once it undergoes initiation?
-The cell can remain static, non diving "arrest" -The cell may possess mutations incompatible with viability or normal function and be targeted for apoptosis -The cell may undergo cell division, resulting in proliferation of the initiated cell
DNA repair mechanisms include
1. Repair of single base mispairs (point mutations) 2. Excision repair 3. End-joining repair of non-homologous DNA
Cancer
A disease resulting from cellular mutation, proliferation, and aberrant cell growth
Following the formation of the DNA-xenobiotic adduct, the persistence of the adduct is?
A major determinate of the outcome of the cell
Mutagenic
Ability to induce changes in genes
Rapid DNA synthesis and cell proliferation (mitosis) in the preneoplastic cells often results in?
Additional genotoxic events such as chromosomal translocations and karyotypic changes
Initiation leads to?
Alterations in DNA sequences (mutations, adducts, deletions)
A carcinogen is?
An agent that exposure to leads to a statistically significant increased incident of neoplasm in a specific tissue
*Oxidative stress
An unbalance between ROS concentration and antioxidants can result in damage to macromolecules -ROS can cause ss or ds breaks in DNA, modifications to purines, pyrimidines, deoxyribose molecules, and/or DNA crosslinks
Retroviruses
Are capable of transforming a normal cell and producing sarcomas
Polyaromatic Hydrocarbons (PAH)
Are found in high levels in charcoal, broiled foods, cig smoke, and diesel exhaust
Examples of metals that exhibit carcinogenicity
Arsenic Beryllium Chromium Lead Nickle Titanium Zinc Iron
Where do non-genotoxic carcinogens usually produce neoplastic effects?
At the target tissue where they are metabolized -Ex. BPA
? Transgenic rodent mutation assays
Based on the gene lac operon (Muta Mouse, Big Blue)
Neoplasms as a result of the progression stage can be?
Benign or malignant
Hormonal mode of action
Biogenic amines, steroids, ect. can cause tissue-specific changes through interaction with a receptor
Carcinogenesis risk depends on?
Both exposure and genetic susceptibility
DNA methylation
Both hyper- and hypo-methylation are associated with carcinogenesis -Tumor suppressing genes that are hyper-methylated are more likely to be found within tumors -Hypo-methylation has bee associated with increased mutation rates (oncogenes tend to be hypo-methylated)
Aromatic Amines and Amides
Can form adducts in proteins and DNA; derivatives of ammonia Found in chemicals (dyes) and drugs
Chromosomal alterations carcinogenic testing
Cells are harvested in their first division after exposure to a toxicant and stained with Giemsa and scored for their completeness of karyotype -Scored for breaks, deletions, rearrangements, translocations, sister chromatid exchanges
When tumor suppressor genes are mutated
Cells can override checkpoints
Initiators or initiating agents are?
Chemical and/or physical toxicants that interact with cellular components at the (first?) stage
What determines the carcinogenic activity of a toxicant?
Chemical stability, transport, and membrane permeability
Repair of single base mispairs (point mutations)
DNA endo-/exo-nucleases clip out mutation, repaired by DNA ligase and DNA polymerase
Excision repair
DNA regions containing chemically modified bases or chemical adducts are repaired by endogenous protein recognition and repair
Non-genotoxic (epigenetic) carcinogens
Exposure to multiple xenobiotics results in tumor formation that is not a result of direct xenobiotic-DNA interactions
Proto-oncogenes
Genes that code for the cell cycle control proteins -Like the gas pedal
Tumor suppressor genes
Genes that stop cell division if conditions are not favorable -Ex. BRCA 1 and 2 -Like the break pedal
Genotoxic carcinogens (direct acting) are?
Highly reactive electrophilic molecules (toxicants) that can interact with and bind to cellular macromolecules, including DNA
DNA viruses
Infection by small DNA viruses is lethal to most nonhost animal cells; however, it is possible for viral DNA to integrate into host genome with cell survival
Stages of carcinogenesis
Initiation Promotion Progression Metastasis
Factors involved in induction of cancerous tumors in humans include
Lifestyle Occupational exposures Medical therapies and/or diagnosis
The process of carcinogenesis involves a series of stages that are clearly definable and reproducible across multiple studies and/or exposures is called?
Multistage carcinogenesis
Is the progression stage reversible?
No
Cytotoxicity
Often results in apoptosis and proliferation, which when rapid, can result in higher incidence of DNA mutation (un-fixed) and resulting tumor formation
When proto-oncogenes mutate, they become
Oncogenes
Classes of geneotoxic carcinogens include
Polyaromatic Hydrocarbons (PAH) Alkylating agents Aromatic Amines and Amides
Alkylating agents
Readily react with DNA; nitrosamines, nitrosourea, sulfonates Found as pollutants; pharmaceuticals
A procarcinogen
Requires biotransformation
Ames assay
Salmonella thyphimurium stains deficient in DNA repair are treated with several doses of the tested compound -Revision to the histidine-positive phenotype is then quantified, which suggest a mutation has occurred through treatment with the test compound
What are some common source ROS molecules?
Superoxide anion Hydroxyl radical Hydrogen peroxide Peroxide
An initiating event becomes "fixed" (permanent) when?
The DNA damage is not repaired prior to DNA synthesis and cell division
Carcinogenesis: Initiation
The first stage of the cancer process -Defined as a stable, potential heritable change
What determines whether a benign or malignant tumor is formed?
The number of mutations and if the tumor suppressor protein is functional
Promotion can be reversible if?
The promoting agent is removed
The production of a proneoplastic lesion is termed?
The promotion phase
Carcinogenesis: Promotion
The second stage of the carcinogenesis process -Proliferation of initiated cells produce proneoplastic lesion.
When proto-oncogenes mutate and become ocogenes
Their proteins no longer properly regulate cell division (generally overstimulate cell division)
Carcinogenesis: Progression
This stage involves the conversion of a benign preneoplastic lesion into neoplastic cancer
Non-geotoxic carcinogens (indirect acting) are?
Toxicants that require subsequent metabolism before they are carcinogenic
Tumor promoters typically show organ specific effects
True
Mitochondrial DNA damage is associated with several different cancers
True Mitochondrial DNA is more susceptible to oxidative base damage than nuclear DNA
Both endogenous and exogenous toxicants that act on a cell to promote proliferation are collectively termed?
Tumor promoters
End-joining repair of non-homologous DNA
When DNA has double strand breaks, it can be repaired by joining the free NDA (non-homologous) ends; or homologous recombination from undamaged homologous chromosome