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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

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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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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 Doull’s “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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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

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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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

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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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 (1950’s)


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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 Doull’s “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 Doull’s “Toxicology”


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Clonal Selection Model

of Neoplastic Progression


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The multistep pathway to colorectal cancer

By B. Vogelstein


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