Page 384 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Carcinogenesis: Mechanisms and Models Chapter | 20 351

VetBooks.ir X-rays; electrons). Human skin can stop α-particles from these ionizations occur in the DNA itself (Adams and
Cox, 1997). Ionizing radiation and oxidative stress are
penetrating and reaching the internal organs. This is
closely associated. Irradiated cells produce damaging
because α-particles deposit most of their energy onto the
skin and may damage the skin in that process, but are reactive oxygen species (ROS), which can cause severe
unable to penetrate any further. Both α- and β-particles damage to cellular macromolecules including nuclear
penetrate cell membranes more easily than they penetrate DNA (Spitz et al., 2004; Wu et al., 1999). A cell’s oxida-
human skin. Therefore, ingesting or inhaling radioactive tive status plays an important role not only at the time of
chemicals that can emit α-or β-particles can pose serious radiation exposure, but also long after exposure.
threats to human health. Irradiation may produce ROS for several minutes or even
In the case of tissue exposure, the energy deposited by hours after exposure (Spitz et al., 2004).
the radiation causes ionizations and the generation of free At the cytological level, the extension of radiation-
radicals, which cause macromolecular damage. Thus, induced DNA damage is chromosome breakage,
high-LET radiations are more destructive to biological nondisjunction of homologous chromosomes, aberrant
materials than low-LET radiations. At the same dose, intrachromosomal crossing over, and scrambling of DNA
low-LET radiations induce the same number of radicals sequences (Adams and Cox, 1997). Therefore, radiation
more sparsely within a cell, whereas high-LET radiations can cause increased genomic instability and the extent of
transfer most of their energy to a small region of the cell. damage is dependent on the energy of the radiation. If an
The localized DNA damage caused by dense ionizations oncogene or a tumor suppressor gene is mutated or
from high-LET radiations is more difficult to repair than severely damaged by radiation, then radiation-induced
the diffuse DNA damage caused by the sparse ionizations damage may have serious consequences.
from low-LET radiations.
Experimental studies with animals as well as epidemi-
ological studies indicate that higher or continual radiation EPIGENETIC BASIS OF CARCINOGENESIS
exposure increases the incidence of specific cancers, such
The mechanisms of carcinogenesis discussed above
as (1) increased incidence of lung cancer among uranium
mostly involve changes in DNA sequence and/or integ-
miners, fluorspar miners, zinc and iron ore miners
rity. However, carcinogenesis has an important epigenetic
(Adams and Cox, 1997); (2) increased occurrence of oste-
component as well. As indicated above, nongenotoxic
osarcoma among workers in luminous dial watch factories
mechanism of carcinogenesis is epigenetic.
(workers licked the paint brush to maintain sharp edges
and in the process consumed radium-226 and radium-228;
the ingested radium deposited in the bone was the source Epigenetic Changes During
of short range α-particles); (3) increased incidence of thy- Carcinogenesis Have Been Widely Studied
roid cancer after the Chernobyl incident (those who con- and Well Documented
tinued to live in the contaminated region and consumed
locally produced milk for the 3 months after the accident, Epigenetic regulation involves heritable changes in gene
had about 85% of the radiation dose to their thyroid from expression that are not accompanied by changes in
iodine-131) (Stsjazhko et al., 1995). Following the DNA sequence. Three main mechanisms of epigenetic
Chernobyl incident, the incidence of thyroid cancer regulation of gene expression are mediated by: (1) DNA
among children under 15 was 30.6 per million during methylation, (2) histone modifications, and (3) RNA
1991 94 as compared to 0.3 during 1981 85. Another interference by small noncoding RNA, such as
source of human data on carcinogenesis by ionizing radia- microRNA (miRNA). Epigenetic changes can collabo-
tion is from the A-bomb survivors from Hiroshima and rate with genetic changes to cause the evolution of a
Nagasaki. Data show that in the first 5 10 years after the cancer because they are mitotically heritable (Jones and
exposure, the risk of leukemia increased rapidly but Baylin, 2007).
declined thereafter. The risk of solid tumors in many Studies over the last 30 years or so have confirmed
organs also increased significantly (Okey et al., 1998). that the genome in a cancer cell is characterized by
genome-wide hypomethylation and site-specific promoter
hypermethylation. Many of these epigenetic changes
The Mechanism of Radiation-Induced
probably occur very early in cancer development and may
Carcinogenesis Involves Severe
contribute to cancer initiation (Jones and Baylin, 2007;
Macromolecular Damage
Sharma et al., 2010).
and Genomic Instability Global DNA hypomethylation basically has two
5
An absorbed dose of 1 Gy generates about 2 3 10 ioniza- effects: it increases genomic instability and activates genes
tions within the mammalian cell. Approximately 1% of including growth promoting genes. Hypomethylation