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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
Excess cancer in Hiroshima A-bomb survivors
50 years follow-up study of approx. 60 000 person
Leukaemia
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
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 ?
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.
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, chromosomale DNA
fragmented
DNA
M.Rosemann, Radiation effects on cells, tissues and organisms
DNA double-strand breaks can result in fixed genetic alterations such as
Chromosomal translocation
V79 cells (Chin. Hamsters ovary cells)
2 Gy gamma-Irradiation, 6 h
or
deletions/losses of DNA (micronuclei)
ROS17/2.8 cells (Osteoblasten, Ratte)
4 Gy gamma-irradiation, 12 h
M.Rosemann, Radiation effects on cells, tissues and organisms
Ionizing radiation causes loss of clonogenic cell survival
0 Gy
1 Gy
(Mouse fibroblast-cells 230kVp-X)
2 Gy
4 Gy
M.Rosemann, Radiation effects on cells, tissues and organisms
Dose / Gy
0
1
2
3
4
5
0
-0.5
-1
-1.5
Log S/So
-2
-2.5
-3
-3.5
-4
-4.5
-5
230kV-Xray
M.Rosemann, Radiation effects on cells, tissues and organisms
Dose / Gy
0
1
2
3
4
5
0
-0.5
-1
-1.5
Log S/So
-2
-2.5
-3
-3.5
-4
-4.5
-5
230kV-Xray
3MeV-De
M.Rosemann, Radiation effects on cells, tissues and organisms
Dose / Gy
0
1
2
3
4
5
0
-0.5
-1
-1.5
Log S/So
-2
-2.5
-3
-3.5
-4
-4.5
-5
4MeV-α
230kV-Xray
3MeV-De
M.Rosemann, Radiation effects on cells, tissues and organisms
Dose / Gy
0
1
2
3
4
0
-0.5
-1
-1.5
Log S/So
-2
-2.5
-3
-3.5
-4
140MeV-Ne
-4.5
-5
4MeV-α
5
M.Rosemann, Radiation effects on cells, tissues and organisms
Dose / Gy
0
1
2
3
4
0
-0.5
-1
-1.5
1200MeV-Xe
Log S/So
-2
-2.5
-3
-3.5
-4
140MeV-Ne
-4.5
-5
4MeV-α
5
M.Rosemann, Radiation effects on cells, tissues and organisms
Relative biological effectiveness (RBE) for
clonogenic cell survival depending on LET
RBE (S/Sx)
8
7
6
5
4
3
2
1
0
2
4
7
10 14 25 64 110 140 170 180 300 420 700
LET (kev/µm)
230kV-Xray
3MeV-De
4MeV-α
140MeV/u-Ne
1200MeV-Xe
M.Rosemann, Radiation effects on cells, tissues and organisms
Relative biological effectiveness (RBE) for
clonogenic cell survival depending on LET
RBE (S/Sx)
8
7
6
Resonance ?
5
4
3
2
1
0
2
4
7
10 14 25 64 110 140 170 180 300 420 700
LET (kev/µm)
230kV-Xray
3MeV-De
4MeV-α
140MeV/u-Ne
1200MeV-Xe
M.Rosemann, Radiation effects on cells, tissues and organisms
Relative biological effectiveness (RBE) for
clonogenic cell survival depending on LET
RBE (S/Sx)
8
7
6
5
4
3
2
1
0
2
4
7
10 14 25 64 110 140 170 180 300 420 700
LET (kev/µm)
230kV-Xray
3MeV-De
4MeV-α
140MeV/u-Ne
1200MeV-Xe
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 BerlinBuch, 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
Radiation-induced changes at Chromosomes
If an essential gene
is lost, cell dies.
Chromatid type
Aberration
Chromosome type
Aberration
S-Phase
Deletion
If no essential gene is lost,
cell might survive
(but might have lost
Tumor-Suppressor-Genes)
Mitosis
Deletion
If a stable translocation
is generated, cell survives
(but might acquire an
activated Oncogens )
Loss of
acentric fragments
Translocation
M.Rosemann, Radiation effects on cells, tissues and organisms
Drosophila-Mutations discovered in
offspring of X-irradiated parental flies
wildtype fruit-fly
mutant (albino)
mutant (white eye)
mutant (inverted body segment)
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
intact, chromosomale DNA
fragmented
DNA
Repair
following 20Gy
0
20’ 40’ 60’ 90’ 2h 3h 5h
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