Transcript BIOLOGICAL EFFECTS OF IONIZING RADIATION AT …

BIOLOGICAL EFFECTS
OF IONIZING RADIATION
AT MOLECULES AND CELLS
The stage of action
of ionizing radiation
Physical stage
The transfer of kinetic energy from ionizing
radiation to atoms or molecules leads to
excitation and ionization of these atoms or
molecules
10 – 16 –
10 – 15
seconds
Physic-chemical The displace of absorbed energy of ionizing
stage
radiation into molecules and between them.
Formation of free radicals
10 – 14 –
10 – 11
seconds
Chemical stage
Reactions between free radicals, reactions
between free radicals and intact molecules.
Formation of molecules with abnormal
structure and function
10 – 6 –
10 – 3
seconds
Biological stage
Formation of injures on all levels – from
cellular structures to organism and population.
Development of processes of biological
damage and reparative processes
Seconds
– years
Effect of radiation
on atom and molecules
Effects of ionizing radiation
at atomic level
Excitation
Ionization
Mechananisms of damage
at molecular level
Direct action
of ionizing radiation
Ionizing radiation + RH
R- + H +
Bond breaks

OH
I
R – C = NH
imidol (enol)

O
Tautomeric shifts
II
R – C = NH2
amide (ketol)
Indirect action
of ionizing radiation
P+
H
X ray
 ray
e-
O
H
OHH+
Ho
OHo
Radiolysis of H2O molecule
Shared electron
Shared electron
H-O-H  H+ + OH- (ionization)
H-O-H  H0 + OH0 (free radicals)
Reaction of H2O molecule
radiolysis
Н2О + h  Н2О+ + еН2О + h  Н2О*  Но + НОо
Н2О + е-  е-гидр  Но + НОН2О + е-  Н2О*  Но + ОНо
о
+
Н2О  Н + ОН
о
+
е +Н Н
о
+
Н2О + ОН  Н2О + ОН
о
+
+
Н2О + Н2О  Н3О + ОН
о
+
Н3О + е  Н2О + Н
Effects of oxygen
on free radical formation
Oxygen can modify the reaction by
enabling creation of other free radical
species with greater stability and longer
lifetimes
H0 + O2  HO20 (hydroperoxy free radical)
R0 + O2  RO20 (organic peroxy free radical)
Reactions with free radicals
H0 + OH0  H2O
H0 + H0  H2
OH0 + OH0  H2O2
RH + OH0  R0 + H2O
RH + H0  R0 + H2
R0 + OH  ROH
R0 + H  RH
R0 + O2  ROO0
ROO0 + RH  ROOH + R0
Lifetimes of free radicals
HO2o
H
RO2o
OHo
o
OHo
3nm
Ho
Because short life of simple free radicals (10-10sec),
only those formed in water column of 2-3 nm around
DNA are able to participate in indirect effect
Relation between linear energy
transfer (LET) and type of action
Direct action is predominant with high
LET radiation, e.g. alpha particles
and neutrons
Indirect action is predominant with
low LET radiation, e.g. X and
gamma rays
Effect of radiation
on biological molecules
Biochemical reactions
with ionizing radiation
DNA is primary target for cell
damage from ionizing radiation
Radiation induced
DNA damage
The most important types of
radiation induced lesions in DNA
Base damage: 1000-2000 per 1 Gy
Single-strand breaks
500-1000 per 1 Gy
Double strand breaks
40-50 per 1 Gy
Mechanisms of base excision
and nucleotide excision repair
Mechanism of single-strand
breaks DNA repair
Endonuclease
1
2
DNA polymerase
3
Exonuclease
4
DNA ligase
5
DNA restoration failure
Unrejoined DNA
double strand breaks
Incorrect repair
of DNA damage
Cytotoxic effect
Mutations
Radiation induced
membrane damage
Effect of radiation
on cells
Types of cellular damage
Norma
Mutation
repair
Interphase
cell death
Mitotic
cell death
Changes of
metabolism
& function
Cell cycle
Radiosensitivity of cell
in cell cycle
M
G1
S
G2 M
Relative survivability of cells irradiated in different phases of
the cell cycle: synchronised cells in late G2 and in mitosis (M)
showed greatest sensitivity to cell killing
Mitotic death
NORMAL
IRRADIATED
Bergonié and Tribondeaus’
‘law’ (1906)
The most
cells are
‘radiosensitive’
 actively proliferating (dividing) at
the time of exposure
 undifferentiated (non-specialized
in structure and function)
Interphase death
Why are peripheral blood lymphocytes highly
sensitive to radiation, although well differentiated?
Morphological forms
of cell death

Pyknosis: The nucleus becomes contracted,
spheroidal, and filled with condensed chromatin.
 Karyolysis: The nucleus swells and loses its
chromatin.
 Protoplasmic Coagulation: Irreversible gelatin
formation occurs in both the cytoplasm and nucleus.
 Karyorrhexis: The nucleus becomes fragmented
and scattered throughout the cell.
 Cytolysis: Cells swell until they burst and then slowly
disappear.
 Apoptosis: Programmed cell death, usually be
fragmentation
Changes of cell metabolism
and function

Block of Mitotic Cycle: Mitosis may be delayed or
inhibited following radiation exposure.

Disruptions in Cell Growth: Cell growth may
also be retarded, usually after a latent period.

Permeability Changes: Irradiated cells may show
both increased and decreased permeability.

Changes in Cell Motility: The motility of a cell
may be decreased following irradiation.
Radiation induced
chromosome damage
Chromosomes
Radiation induced
chromosomal aberrations
Relative cellular
radiosensitivity
 Vegetative Cells: these cells, comprising differentiated functional
cells of a large variety of tissues, are generally the most
radiosensitive.
 Differentiating Cells: these cells are somewhat less sensitive to
radiation; they are relatively short-lived and include the first
generation produced by division of the vegetative mitotic cells.
 Totally Differentiated Cells: these cells are relatively
radioresistant; they normally have relatively long lifespans and do
not undergo regular or periodic division in the adult stage, except
under abnormal conditions such as following damage to or
destruction of a large number of their own kind.
 Fixed Nonreplicating Cells: these cells are most radioresistant;
they are highly differentiated morphologically and highly
specialized in function.
Summary of lection
• Cells going through the division phase (M and
S) are generally the most sensitive to ionizing
radiation. Exceptions: lymphocytes and some bone
marrow stem cells, which exhibit interphase death
• Bone marrow consists of progenitor and stem
cells, the most radiosensitive cells in the
human body and the most important in
controlling infection
Lecture is ended
THANKS FOR ATTENTION
In lecture materials
of the International Atomic Energy Agency (IAEA),
kindly given by doctor Elena Buglova, were used