Toxicology Exam 4

Benign Tumors

Are not cancerous → do not spread to other parts of the body & typically do not return after removal

Malignant Tumors

Are cancerous → can invade nearby tissues & spread to other parts of the body (metastasis)

Cells break off and spread through the bloodstream

Genotoxic

Damage DNA

Nongenotoxic

Do not damage DNA → can contribute to cancer formation by changing gene expression/cell function

List and describe the three possible fates of an initiated cell

1. May remain in static, non-dividing state

2. Undergo apoptosis

3. Undergo proliferation (→ promotion)

Initiation

1st stage of carcinogenesis

Stable, heritable (passed through cell division) changes in DNA

Rapid, irreversible

Genotoxic carcinogens initiate DNA damage

Initiators bind to DNA to form adducts (not recognizable) → mutations

Initiating event becomes “fixed” (part of the genome) if not repaired for division

Promotion

2nd stage of carcinogenesis

Proliferation of initiated cells

Nongenotoxic carcinogens act as tumor promoters → can be exogenous (toxicants) or endogenous (hormones)

Tissue specific

Promotion is reversible upon removal of agent

Tumor promoters → gene expression that increases proliferation & decreases apoptosis

Progression

3rd stage of carcinogenesis

Conversion of a benign preneoplastic lesion → neoplasm (malignant transformation)

Irreversible → must be removed

Increased proliferation → more DNA damage

Direct-Acting Genotoxic Carcinogens

Agent directly binds to DNA (no activation required)

Indirect-Acting Genotoxic Carcinogens

Metabolite of agent binds to DNA (metabolism required)

Procarcinogens produce effects at site of metabolism

Explain the importance of DNA repair in carcinogenesis

If cell division occurs before DNA damage is repaired → mutations will be passed on

Mutations can impair cell function (altered proteins)

Cytotoxicity

Nongenotoxic mechanism

Production of sustained cell death

Metabolism of chemical often accompanied by rapid regenerative growth/proliferation → cancer

Receptor-Mediated

Nongenotoxic mechanism

Some carcinogens activate receptors within the cell 

Act as transcription factors expressing genes that increase proliferation, decrease apoptosis & cell communication

CAR, PPAR, AhR

Hormonal Mode of Action

Nongenotoxic mechanism

Hormonally active chemicals active hormone receptors → induce proliferation in target tissue

Diethylstilbesterol (DES) & bisphenol-A (BPA) activate estrogen receptors (endocrine disruptors)

DNA Methylation

Nongenotoxic mechanism

Introduces CH3 to specific DNA bases → changes gene activity/expression

High DNA methylation = decreased gene expression (methylation of gene involved in apoptosis → cancer)

Carcinogens can affect DNA methylation

Oxidative Stress

Nongenotoxic mechanism

Production of reactive oxygen species (ROS) → DNA damage

Normal metabolism, exogeneous chemicals, radiation & metals (focuses on toxicants INDUCING ROS, NOT the ROS itself)

Can be balanced by antioxidants

Proto-Oncogenes

Genes involved in normal cell growth/division

Oncogenes = Mutated to be activated → increased cell growth/division

Genetically dominant = only need one mutated copy

Tumor-Suppressor Genes

Genes involved in normal inhibition of cell growth/division

Mutations resulting in inactivation → inability to prevent cell growth/division

Genetically recessive = need two mutated copies

List factors implicated in human cancers and give an example of each

1. Infectious agents (RSV/HPV)

2. Lifestyle (recreational drug use, diet)

3. Medical treatment (X-rays, chemotherapy, medications)

4. Environmental exposure (UV radiation, cigarette smoke, PAHs)

5. Occupational exposure (benzene, arsenic)

Explain the term transformation

Transformation is when a benign cell is transformed into a cancerous/malignant cell

List the classes of genotoxic carcinogens

1. Polyaromatic Hydrocarbons (PAHs)

2. Alkylating Agents

3. Aromatic Amines & Amides

Thalidomide

Prescribed in the 1950s to treat morning sickness in pregnant women

Resulted in children born with malformations (no effect on adult humans/animals)

Diethylstilbestrol (DES)

Synthetic estrogen used in the US from 1940-1970 to prevent miscarriages

Linked to reproductive abnormalities in female/male offspring

Ethanol

Fetal Alcohol Syndrome (FAS) - Craniofacial dysmorphia, slowed intellectual development & growth

Fetal Alcohol Spectrum Disorder (FASD) - Effects can occur at lower ethanol doses than FAS

Tobacco Smoke

25% of women continue to smoke during pregnancy → spontaneous abortion, perinatal deaths, SIDS, low birth weight, cognitive disorders

List the 3 major effects of toxicant exposure during development

1. Embryo lethality

2. Malformations

3. Growth slowing

Explain the importance of apoptosis during morphogenesis

Apoptosis plays a critical role in normal morphogenesis (leads to the formations of digits)

Has to be a delicate balance between proliferation (growth) & apoptosis (formation in specific regions)

Describe how maternal toxicokinetics changes during pregnancy

1. Increased residency time of ingesta (nutrients) in the upper GI

2. Cardiac output increases by 50% initially (heart working harder)

3. Increased blood volume

4. 70% elevation in extracellular space

→ changes in volume of blood distribution & amounts of toxicants bound by plasma

List maternal susceptibility factors for abnormal fetal development

1. Genetics

2. Age

3. Disease

4. Nutrition

5. Stress

6. Placental/maternal toxicity