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