Environmental health carcinogenesis
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Environmental Health Carcinogenesis. Week 7. Genotoxicity: toxic effects on genetic material. Cancer Developmental (gestational timing crucial) Somatic diseases . The nature of “life information”…. DNA structure Base-sugar-triphosphate Purines: A, G; Pyrimidines: C, T(U)

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Environmental health carcinogenesis l.jpg

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) --> 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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Mutagens:agents 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)(>10-10m)

    • Thymine dimerization (T-T)

    • Cytosine hydration (C + H2O)

  • Ionizing radiation

    (x/  -rays, <10-10m; ,  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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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 Doull’s “Toxicology”

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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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Causes of Death

All causes

Unintentional injuries


Heart disease

Suicide, homicide

Congenital anomalies

Years of Life Lost*







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

* 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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Usually encapsulated

Usually non-invasive

Highly differentiated

Rare mitoses

Slow growth

Little or no anaplasia

No metastases




Poorly differentiated

Mitoses relatively common

Rapid growth

Anaplastic to varying degrees


Malignant vs. Benign Neoplasms

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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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Genotoxic Non-genotoxic

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Many different

chemical structures

are carcinogenic

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molecules with

carcinogenic properties

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Millers showed that metabolic activation

is key to carcinogenicity (1950’s)

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Reactive metabolites bind covalently to DNA

and form adducts which can generate mutations

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Carcinogenesis protection

  • 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 Doull’s “Toxicology”

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Tumor promoters tumor development

TPA is the experimental

skin tumor promoter

found in croton oil

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Liver tumor incidence after daily tumor development

doses of 2-acetylaminofluorene

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Tumor response on mice initiated with 0.2 tumor development mol

of dimethylbenzanthracene and promoted with


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Potency of carcinogens tumor development

  • 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 Doull’s “Toxicology”

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Clonal Selection Model tumor development

of Neoplastic Progression

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The multistep pathway to colorectal cancer tumor development

By B. Vogelstein