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M.Rosemann, Radiation effects on cells, tissues and organisms
Radiation-effects on cells and tissues
M.Rosemann
National Center for Radiation Sciences
Helmholtz-Center for Health and Environment
M.Rosemann, Radiation effects on cells, tissues and organisms
Radiation - Carcinogenesis initial medical and epidemiological observations
1902: A.Frieben: Demonstration lines cancroides of the upper side of the hand, that developed
after long-term exposure to diagnostic X-rays.
in: Fortschritte auf dem Gebiet der Röntgenstrahlung 6, 106ff
16th century: unusual high incidence of fatal lung diseases among silver and tin miners in
the Erz Mountains of Saxonia (report of the local physician G.Agricola)
was termed: Schneeberger Lung Disease
1937: lung cancer in miners was associated with Radon exposure of lung epithelium
(B. Rajewski)
since 1947: Radiation Effects Research Foundation (RERF) monitoring cancer incidenc
in A-bomb survivors of Hiroshima and Nagasaki
(RERF Foundation, Preston and Pierce, Radiation Research 160, 2003)
M.Rosemann, Radiation effects on cells, tissues and organisms
Leukaemia
Excess cancer in Hiroshima A-bomb survivors
50 years follow-up study of approx. 60 000 person
per 1Sv
• Gamma- and neutron irradiation, single acute exposure, 0.2 – 3 Sv
• allmost all organs affected
• highest risk for continuously proliferating tissues
(breast, skin, colon, juvenil thyroid, haematopoeitic system)
M.Rosemann, Radiation effects on cells, tissues and organisms
The energy of ionizing radiation is deposited in living matter
in the form of discret ionisations.
Their spatial pattern match the structure of the DNA double-helix.
Ionizing radiation thus has a high efficiancy to produce DNA breaks.
DNA is a single-copy molecule
Chromosomal DNA with a Mr > 6x104 kDa is several hundred times
larger than the largest protein and has thus the biggest target size.
DNA – the primary target of
radiation damage
A - dose of about 2 Gy deposits in the entire exposed
human body about 150 Joule energy
(less than the thermal energy of a cup of hot coffee).
Why than has ionizing radiation such a sever biological
effect ?
M.Rosemann, Radiation effects on cells, tissues and organisms
DNA – lesions are specific for the genotoxic agent
DNA double strand break
is the most severe DNA
lesion
M.Rosemann, Radiation effects on cells, tissues and organisms
Initial radiation effect causes DNA fragmentation by double-strand breaks
Dose [Gy] 0 0.2 0.5 1 2 5 10 20
intact, chromo-
somale DNA
fragmented
DNA
M.Rosemann, Radiation effects on cells, tissues and organisms
V79 cells (Chin. Hamsters ovary cells)
2 Gy gamma-Irradiation, 6 h
ROS17/2.8 cells (Osteoblasten, Ratte)
4 Gy gamma-irradiation, 12 h
DNA double-strand breaks can result in fixed genetic alterations such as
Chromosomal translocation or deletions/losses of DNA (micronuclei)
M.Rosemann, Radiation effects on cells, tissues and organisms
Ionizing radiation causes loss of clonogenic cell survival
0 Gy 1 Gy 2 Gy 4 Gy
(Mouse fibroblast-cells 230kVp-X)
M.Rosemann, Radiation effects on cells, tissues and organisms
-5
-4.5
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3 4 5
Dose / Gy
Log S/So
230kV-Xray
M.Rosemann, Radiation effects on cells, tissues and organisms
-5
-4.5
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3 4 5
Dose / Gy
Log S/So
230kV-Xray 3MeV-De
M.Rosemann, Radiation effects on cells, tissues and organisms
-5
-4.5
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3 4 5
Dose / Gy
Log S/So
230kV-Xray 3MeV-De
4MeV-α
M.Rosemann, Radiation effects on cells, tissues and organisms
-5
-4.5
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3 4 5
Dose / Gy
Log S/So
4MeV-α
140MeV-Ne
M.Rosemann, Radiation effects on cells, tissues and organisms
-5
-4.5
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3 4 5
1200MeV-Xe
4MeV-α
140MeV-Ne
Dose / Gy
Log S/So
M.Rosemann, Radiation effects on cells, tissues and organisms
Relative biological effectiveness (RBE) for
clonogenic cell survival depending on LET
0
1
2
3
4
5
6
7
8
2 4 7 10 14 25 64 110 140 170 180 300 420 700
LET (kev/µm)
RBE (S/Sx)
230kV-Xray 3MeV-De 4MeV-α 1200MeV-Xe 140MeV/u-Ne
M.Rosemann, Radiation effects on cells, tissues and organisms
0
1
2
3
4
5
6
7
8
2 4 7 10 14 25 64 110 140 170 180 300 420 700
LET (kev/µm)
RBE (S/Sx)
230kV-Xray 3MeV-De 4MeV-α 1200MeV-Xe 140MeV/u-Ne
Resonance ?
Relative biological effectiveness (RBE) for
clonogenic cell survival depending on LET
M.Rosemann, Radiation effects on cells, tissues and organisms
0
1
2
3
4
5
6
7
8
2 4 7 10 14 25 64 110 140 170 180 300 420 700
LET (kev/µm)
RBE (S/Sx)
230kV-Xray 3MeV-De 4MeV-α 1200MeV-Xe 140MeV/u-Ne
Relative biological effectiveness (RBE) for
clonogenic cell survival depending on LET
M.Rosemann, Radiation effects on cells, tissues and organisms
Radiation mutagenesis and the prediction of DNA target
N. Timmofeev-Ressovsky (working at Kaiser-Wilhelm Institute in Berlin-
Buch, 1928-1945) tested various radiation qualities for their mutagenic
potential on Drosophila.
Measuring mutation and the ionisation pattern in parallel, he concluded
1935 (together with Zimmer and Delbrueck) that the sensitive target in the
cell is a single molecule of about 5 – 20 nm in diameter (cross-section)
Their monography „On the natur of gene-mutations and the structure of
genes“ inspired E. Schröder („what is life“) and prompted J.Watson and
F.Crick discovering DNA as the molecular base of inheritance.
M.Rosemann, Radiation effects on cells, tissues and organisms
Chromatid type
Aberration
S-Phase Mitosis
Loss of
acentric fragments
If an essential gene
is lost, cell dies.
If no essential gene is lost,
cell might survive
(but might have lost
Tumor-Suppressor-Genes)
Trans-
location
If a stable translocation
is generated, cell survives
(but might acquire an
activated Oncogens )
Radiation-induced changes at Chromosomes
Chromosome type
Aberration
Deletion
Deletion
M.Rosemann, Radiation effects on cells, tissues and organisms
wildtype fruit-fly
mutant (albino)
mutant (white eye)
mutant (inverted body segment)
Drosophila-Mutations discovered in
offspring of X-irradiated parental flies
M.Rosemann, Radiation effects on cells, tissues and organisms
Initial radiation effect causes DNA fragmentation by double-strand breaks
Living cells can repair most of these damages
Dose [Gy] 0 0.2 0.5 1 2 5 10 20
Repair 0 20’ 40’ 60’ 90’ 2h 3h 5h
following 20Gy
intact, chromo-
somale DNA
fragmented
DNA
M.Rosemann, Radiation effects on cells, tissues and organisms
The Radium-Dial Painters (US Radium Corporation)
painting of aircraft-instruments
with radioactive-fluorescence
ink
accidental oral uptake of Ra226
(10-1000µCi/year, T1/2=1600 y)
accumulation in all skeletal
regions (earth alkaline metal
incorporated into bone similar
to calcium)
http://www.lastfm.de/music/Kraftwerk/_/Radioaktivit%C3%A4t
M.Rosemann, Radiation effects on cells, tissues and organisms
Radiation-induced Osteosarcoma in mice
224 Ra
Primary Osteosarcoma
M.Rosemann, Radiation effects on cells, tissues and organisms
Th227 induced Osteosarcomas in mice:
radiological and histological appearance
Histology using
EvG staining
Murine radiogenic osteosarcomas resemble human spontaneous bone tumours
(Gössner et al 1976).
M.Rosemann, Radiation effects on cells, tissues and organisms
Synopsis:
Radiation acts primarily on the cellular DNA.
It causes with high efficiancy DNA breaks
Long persistant effects are
• Cell killing
• Chromosomal damage
• Mutations
• Cancer