Environmental Health Carcinogenesis

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Environmental Health Carcinogenesis

• Week 7

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Genotoxicity toxic effects on genetic material

• Cancer
• Developmental
• (gestational timing crucial)
• Somatic diseases

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The nature of life information

• DNA structure
• Base-sugar-triphosphate
• Purines A, G Pyrimidines C, T(U)
• Double helix A-T C-G pairs
• Chromosomes (with chromatin)
• Humans 23 autos. pairs sex pair (XY, XX)
• DNA (code) --gt protein 3nucleic acids /1
  aminoacid
• Universal code - the same principles and
  molecules in every organism (amoebas to humans)
• Genes (units of information) are the same in
  every cell of an organism, but expression of
  genes varies by cell/tissue
• Conserved and variable regions of code

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Types of Genotoxic effects

• Chromosomal aberrations
• Deletions
• Duplications
• Inversions
• Translocations
• Sister chromatid exchanges
• Gene mutations
• Point mutations (base replacement)
• Frameshift mutations
• (insertion/deletion of part of gene)

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Mutagensagents that cause a mutation

• Mutation Alteration in the genetic code (DNA
  sequence of nucleotides), that may result in
  altered population of cells or organisms (nucleic
  DNA most important)
• Mutations
• Adaptation/survival and speciation
• Disease and death

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Effects of mutations

• Silent - no effect
• Change in gene expression
• protein amount, location, timing
• Change in structure of protein
• Single aminoacid change (especially
  hydrophilic-phobic)
• Multiple aminoacids/Trancation
• Change or loss of activity
• Inefficient or improper biochemical process
• Altered cell function
• Disease cancer birth defects hereditary
  diseases

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Genotoxic factors

• UV light (200-300nm) (gt10-10m)
• Thymine dimerization (T-T)
• Cytosine hydration (C H2O)
• Ionizing radiation
• (x/ ? -rays, lt10-10m ?, ? particles)
• Single strand, double strand breaks, base changes
• Biotoxins (aflatoxin-B1)
• Viruses (HPV)

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More genotoxic factors

• Chemicals
• Alkylating (diethylnitrosamine)
• Mispairing (G-T vs G-C)
• Depurination (transition, transversion)
• Backbone break
• Arylating (forming DNA adducts)
• Intercalating (planar aromatic hydrocarbons)
• Base analogues (5-Br-uracil 5-F-uracil)
• Metaphase blockers
• Deamination agents
• Enzyme inhibitors
• Metals (As, Be, Cd, Cr(IV, V), Ni, Pb)

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Types of DNA damage
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Reactive oxygen species
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Post genetic-damage events

• Repair
• Apoptosis
• Permanent change
• Cell level
• Tissue level
• Organism level
• Species level

See also p. 64 and 262 of Casarett and Doulls
Toxicology
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Extensive DNA repair system
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Cancer, a.k.a. malignant neoplasm

• Uncontrolled growth and spread of abnormal cells
• Solid tumors liver, lung, intestine, breast, etc
• Blood and lymphatic system, incl. bone marrow
• Reasons for increased cancer incidence
• increased age
• increased number of carcinogens present
• other?

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Cancer is the leading disease-related cause of
years of life lost in the US.

• Causes of Death
• All causes
• Unintentional injuries
• Cancer
• Heart disease
• Suicide, homicide
• Congenital anomalies

• Years of Life Lost
• 11,761,000
• 2,306,000
• 1,803,000
• 1,563,000
• 1,247,000
• 584,000

Estimated years of life lost before the age of
65
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Carcinogenesis Terms

• Chemical Carcinogenesis is the chemically-induced
  generation of cancerous growths in living
  organisms. Cancerous growths are often called
  neoplasms.
• A neoplasm is an abnormal tissue mass, the growth
  of which exceeds and is uncoordinated with that
  of normal tissue and persists in a similar manner
  following cessation of stimulus. Unique feature
  is the continuous replication of a cell
  population.

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Cancer is therefore the malignant uncontrolled
proliferation of neoplastic cells. Also a
description of a multitude of different disease
states (200)
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Malignant vs. Benign Neoplasms

• Benign
• Usually encapsulated
• Usually non-invasive
• Highly differentiated
• Rare mitoses
• Slow growth
• Little or no anaplasia
• No metastases

• Malignant
• Encapsulated
• Invasive
• Poorly differentiated
• Mitoses relatively common
• Rapid growth
• Anaplastic to varying degrees
• Metastases

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The many faces of cancer
Malignant neoplasms are usually called
carcinomas (endo- or ectoderm) or
sarcomas (mesoderm). Exceptions are hematopoietic
malignancies, melanoma, neuroblastoma, thymoma.
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Carcinogens

• Genotoxic Non-genotoxic

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Many different chemical structures are
carcinogenic
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Natural/endogenous molecules with carcinogenic
properties
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Synthetic hormone-like structures
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Millers showed that metabolic activation is key
to carcinogenicity (1950s)
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metabolic activation, continued
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Activation can occur also following Phase II
reactions
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Reactive metabolites bind covalently to DNA and
form adducts which can generate mutations
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adducts, continued
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adducts, continued
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Effective elimination of carcinogens is a means
of protection
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Carcinogenesis

• Initiation
• Dose related
• Dividing cells in site are targets
• Genetic damage on expressed genes
• Can be repaired
• Promotion
• Activation of initiated cell
• First cell of tumor
• Progression
• Rapid (relatively) expansion of abnormal cells

See also p. 267, 271, 275 of Casarett and Doulls
Toxicology
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Initiation and promotion
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Polyaromatic hydrocarbons (PAHs) are initiating
agents in tumor development
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Tumor promoters TPA is the experimental skin
tumor promoter found in croton oil
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Liver tumor incidence after daily doses of
2-acetylaminofluorene
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Tumor response on mice initiated with 0.2?mol of
dimethylbenzanthracene and promoted with
12-O-tetradecanoylphorbol-13-acetate
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Potency of carcinogens

• Defined as the slope of the dose-response curve
  for induction of neoplasms
• Iball index ( animals with tumors)
• TD50 (used in comparative list)
• T25 (dose rate that gives 25 of neoplasms at
  specific site)

See also p. 301 of Casarett and Doulls
Toxicology
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Clonal Selection Model of Neoplastic Progression
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The multistep pathway to colorectal cancer
By B. Vogelstein