Radiation-effects on cells and tissues · M.Rosemann, Radiation effects on cells, tissues and organisms Initial radiation effect causes DNA fragmentation by double-strand breaks Living

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


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)


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)


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 ?


DNA – lesions are specific for the genotoxic agent

DNA double strand break

is the most severe DNA

lesion


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


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)


Ionizing radiation causes loss of clonogenic cell survival

0 Gy 1 Gy 2 Gy 4 Gy

(Mouse fibroblast-cells 230kVp-X)


-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


-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


-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


-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


-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


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


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)


Resonance ?




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)





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.


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


wildtype fruit-fly

mutant (albino)

mutant (white eye)

mutant (inverted body segment)

Drosophila-Mutations discovered in

offspring of X-irradiated parental flies


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


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

http://www.lastfm.de/music/Kraftwerk/_/Radioaktivit%C3%A4t


Radiation-induced Osteosarcoma in mice

224 Ra

Primary Osteosarcoma


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).


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

Documents

Radiation-effects on cells and tissues · M.Rosemann, Radiation effects on cells, tissues and organisms Initial radiation effect causes DNA fragmentation by double-strand breaks Living