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)– 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

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)

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

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

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)

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)

Types of DNA damage

Reactive oxygen species

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”

Extensive DNA repair system

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?

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

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.

Cancer is therefore the malignant uncontrolled

proliferation of neoplastic cells. Also a description of a

multitude of different disease states (~200)

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

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

Carcinogens

Genotoxic Non-genotoxic

Many different chemical structures are carcinogenic

Natural/endogenous molecules with

carcinogenic properties

Synthetic hormone-like structures

Millers showed that metabolic activation is key to carcinogenicity (1950’s)

…metabolic activation, continued

Activation can occur also following Phase II reactions

Reactive metabolites bind covalently to DNA and form adducts which can generate mutations

…adducts, continued

…adducts, continued

Effective elimination of carcinogens is a means of protection

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”

Initiation and promotion

Polyaromatic hydrocarbons (PAHs) are initiating agents in tumor development

Tumor promotersTPA is the experimental

skin tumor promoter found in croton oil

Liver tumor incidence after daily doses of 2-acetylaminofluorene

Tumor response on mice initiated with 0.2mol of dimethylbenzanthracene and promoted with

12-O-tetradecanoylphorbol-13-acetate

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”

Clonal Selection Model of Neoplastic Progression

The multistep pathway to colorectal cancer

By B. Vogelstein