☢️Radiobiology Unit 7 – Radiation–Induced Chromosomal Aberrations

Key Concepts and Terminology

• Ionizing radiation includes high-energy particles or electromagnetic waves (X-rays, gamma rays) that can ionize atoms or molecules
• Non-ionizing radiation lacks sufficient energy to ionize atoms or molecules (radio waves, microwaves, visible light)
• Linear energy transfer (LET) measures the amount of energy deposited per unit length of the radiation track
  • High LET radiation (alpha particles, neutrons) causes dense ionization events along its path
  • Low LET radiation (X-rays, gamma rays) produces sparse ionization events
• Relative biological effectiveness (RBE) compares the biological damage caused by different types of radiation relative to a reference radiation (usually X-rays or gamma rays)
• Direct action occurs when radiation directly interacts with critical targets in cells (DNA, proteins)
• Indirect action involves the formation of reactive chemical species (free radicals) that can damage cellular components
• Chromosomal aberrations are structural changes in chromosomes induced by radiation exposure
• Dosimetry quantifies the absorbed radiation dose in terms of energy deposited per unit mass of tissue (gray, Gy)

Types of Radiation and Their Effects

• Electromagnetic radiation includes X-rays and gamma rays
  • X-rays are produced by electron transitions in atoms or by deceleration of charged particles
  • Gamma rays originate from nuclear transitions or radioactive decay
• Particulate radiation consists of subatomic particles
  • Alpha particles are helium nuclei emitted during radioactive decay
  • Beta particles are high-energy electrons or positrons emitted during radioactive decay
  • Neutron radiation occurs from nuclear fission or fusion reactions
• Ultraviolet (UV) radiation is a form of non-ionizing radiation that can cause DNA damage and mutations
• Radiation effects depend on the type, energy, and dose of radiation
  • Ionizing radiation can cause direct DNA damage, leading to mutations and chromosomal aberrations
  • Non-ionizing radiation typically induces indirect cellular damage through the generation of reactive oxygen species
• Radiation can induce single-strand or double-strand breaks in DNA
• Radiation exposure can lead to oxidative stress and inflammation in cells and tissues

Chromosomal Structure and Function

• Chromosomes are highly condensed structures that contain genetic material (DNA) and proteins
• DNA is wrapped around histone proteins to form nucleosomes, which are further compacted into higher-order structures
• Chromatin refers to the complex of DNA and proteins that make up chromosomes
  • Euchromatin is loosely packed and transcriptionally active
  • Heterochromatin is tightly packed and transcriptionally inactive
• Centromeres are specialized regions that play a role in chromosome segregation during cell division
• Telomeres are protective structures at the ends of chromosomes that maintain chromosomal stability
• Sister chromatids are identical copies of a chromosome held together by the centromere
• Chromosomes replicate during the S phase of the cell cycle
• Chromosomal integrity is essential for proper gene expression and cellular function

Mechanisms of Radiation-Induced Damage

• Radiation can cause direct damage to DNA by inducing strand breaks, base modifications, and cross-links
• Indirect damage occurs through the formation of reactive oxygen species (ROS) and free radicals
  • ROS can oxidize DNA bases, leading to mutations and strand breaks
  • Free radicals can also damage proteins and lipids, disrupting cellular processes
• Double-strand breaks (DSBs) are the most critical type of DNA damage induced by radiation
  • DSBs can lead to chromosomal aberrations if not repaired correctly
• Radiation can induce oxidative stress and alter cellular signaling pathways
• Radiation-induced bystander effect occurs when irradiated cells release signals that affect nearby unirradiated cells
• Adaptive response refers to the phenomenon where low doses of radiation can induce protective mechanisms against future radiation exposure
• Radiation can cause epigenetic changes, such as alterations in DNA methylation and histone modifications
• Mitochondrial DNA is particularly susceptible to radiation-induced damage due to its proximity to ROS generation sites

Classification of Chromosomal Aberrations

• Chromosomal aberrations are classified based on their structure and origin
• Numerical aberrations involve changes in the number of chromosomes
  • Aneuploidy refers to the gain or loss of one or a few chromosomes (trisomy, monosomy)
  • Polyploidy is the presence of extra sets of chromosomes (triploidy, tetraploidy)
• Structural aberrations involve changes in the structure of chromosomes
  • Deletions are losses of chromosomal segments
  • Duplications involve the repetition of a chromosomal segment
  • Inversions occur when a chromosomal segment is reversed in orientation
  • Translocations involve the exchange of chromosomal segments between non-homologous chromosomes
• Chromatid-type aberrations affect one of the sister chromatids and are induced by ionizing radiation in the S or G2 phases of the cell cycle
• Chromosome-type aberrations affect both sister chromatids and are induced by ionizing radiation in the G1 phase of the cell cycle
• Complex aberrations involve multiple breaks and rearrangements in chromosomes

Detection and Analysis Methods

• Cytogenetic techniques are used to visualize and analyze chromosomal aberrations
• Karyotyping involves the arrangement of chromosomes in a standardized format for microscopic analysis
  • Chromosomes are stained with Giemsa or other dyes to produce distinct banding patterns
• Fluorescence in situ hybridization (FISH) uses fluorescently labeled DNA probes to detect specific chromosomal regions or aberrations
  • Multicolor FISH (mFISH) allows the simultaneous detection of all chromosomes using different fluorescent labels
• Chromosome painting involves the use of chromosome-specific DNA probes to visualize individual chromosomes
• Spectral karyotyping (SKY) combines chromosome painting with spectral imaging to identify complex chromosomal rearrangements
• Comparative genomic hybridization (CGH) compares the DNA content of a test sample with a reference sample to detect copy number variations
• Next-generation sequencing (NGS) technologies enable high-resolution analysis of chromosomal aberrations at the molecular level
• Micronucleus assay detects small nuclei formed by chromosomal fragments or whole chromosomes that are not incorporated into the main nucleus during cell division

Biological Consequences and Health Risks

• Chromosomal aberrations can have significant biological consequences and health implications
• Chromosomal instability is a hallmark of cancer and can lead to the accumulation of genetic alterations
• Aneuploidy is associated with developmental disorders (Down syndrome) and cancer progression
• Structural aberrations can disrupt genes or create fusion genes, leading to altered gene expression and protein function
• Radiation-induced chromosomal aberrations can increase the risk of cancer development
  • Specific translocations are associated with certain types of leukemia and lymphoma (Philadelphia chromosome in chronic myeloid leukemia)
• Chromosomal aberrations can lead to infertility or reproductive disorders
• Radiation exposure during pregnancy can cause chromosomal abnormalities in the developing fetus, leading to congenital disabilities
• Chromosomal aberrations can serve as biomarkers of radiation exposure and can be used for dose estimation in radiation accidents or occupational exposures
• Individual susceptibility to radiation-induced chromosomal damage varies based on genetic factors and DNA repair capacity

Applications in Research and Medicine

• Chromosomal aberrations are studied to understand the mechanisms of radiation-induced DNA damage and repair
• Analysis of chromosomal aberrations is used to assess the genotoxicity of environmental agents and chemicals
• Chromosomal aberrations serve as biomarkers for monitoring populations exposed to radiation or genotoxic agents
• Cytogenetic techniques are used in prenatal diagnosis to detect chromosomal abnormalities in fetuses
• Chromosomal analysis is important in the diagnosis and prognosis of hematological malignancies and solid tumors
• Targeted therapies can be developed based on specific chromosomal aberrations (imatinib for Philadelphia chromosome-positive leukemia)
• Chromosomal aberrations are used to study the effects of radiation on human health and to establish radiation protection guidelines
• Induced pluripotent stem cells (iPSCs) derived from patients with chromosomal disorders are used to model diseases and develop personalized therapies
• Chromosomal aberrations are employed in evolutionary studies to understand the role of chromosomal rearrangements in speciation and adaptation