放射防护学课件：Chapter 2 Radiation Biology

1、Chapter 2: Radiation Biology （Radiobiology）Contents：1- the biological effect of irradiation2- the main factors to influence the effect of irradiation3- the effect of irradiation on biological chemistry4- the effect of irradiation on cells5- the effect of irradiation on blood and Hematopoietic system

2、6- the effect of irradiation on immune system7- radiation injury on skin8- stochastic and deterministic effectsRadiation Biology (also known as Radiobiology), as a field of clinical and basic medical sciences, originated from Leopold Freunds 1896 demonstration of the therapeutic treatment of a hairy

3、 mole using a new type of electromagnetic radiation called x-rays, which was discovered 1 year previously by the German physicist, Wilhelm Rntgen. At the same time, Pierre and Marie Curie discovered the radioactive polonium and radium later used to treat cancer. In simplest terms, radiobiology is th

4、e study of the action of ionizing radiation on living things. Thefactthationizingradiationproducesbiologicaldamagehasbeenknownformanyyears.*ThefirstcaseofhumaninjurywasreportedintheliteraturejustafewmonthsfollowingRoentgensoriginalpaperin 1895announcingthediscoveryofx-rays.*Asearlyas1902,thefirstcas

5、eofx-rayinducedcancerwasreportedintheliterature.*Earlyhumanevidenceofharmfuleffectsasaresultofexposuretoradiationinlargeamountsexistedinthe1920sand1930s,basedupontheexperienceofearly radiologists,minersexposedtoairborneradioactivityunder ground,personsworkingintheradiumindustry,andotherspecialoccupa

6、tionalgroups.*Thelong-termbiological significanceofsmaller,repeateddosesofradiation,however,wasnotwidelyappreciateduntilrelativelyrecently,andmost ofourknowledgeofthebiologicaleffectsofradiationhasbeenaccumulatedsinceWorldWarII.Biological Effects of Ionizing Radiation（电离辐射生物效应） After the effects of

7、ionizing radiation on the body, the energy transfer to the molecules, cells, tissues and organs and cause morphological and functional changes, known as the biological effect of radiation.Ion formation H2O+ and e-Excitation and H and OH radical formationION RADICAL LIFETIMEFREE RADICAL LIFETIMEBREAK

8、AGE OF BONDSCHEMICAL REPAIR / MISREPAIRENZYMIC REPAIR / MISREPAIREARLY BIOLOGICAL EFFECTSLATE BIOLOGICAL EFFECTS10-1810-1210-6100106SECSAbsorption of energyPhysical effectsChemical lesions Chemical repairEnzyme repair/lesionCellular effectsTissue effectsSystemic effectsDays-YearsHrs-DaysMins-HrsThe

9、time effect of biological action of radiation Ion - atom or molecule that has lost an electron and is charged. Free radical - atom or group of atoms that contains an unpaired electron and is highly reactive Aqueous electron - has lost kinetic energy and has been captured by water - a powerful reduci

10、ng agent.10-1610-14Direct and Indirect Action of RadiationIndirectly ionizing radiation can act directly or indirectly on biological targetsIf the ion pairs and free radicals are produced in a biologic target (DNA) then this is direct actionIf water or other atoms or molecules are ionized, diffusibl

11、e free radicals can act as intermediaries to cause damage - this is indirect actionIonizing radiation (IR) can act on biological molecules (RH, representative of hydrocarbons) by causing ionization and excitation. One or more chemical bonds may be broken giving atoms or molecules with unpaired elect

12、rons, which are very reactive and have a short life. -The formation of these radicals occurs in the picosecond time range after the passage of the photons. -The bond may be repaired or cross-linking may occur due to radical-radical reactions. -These free radicals may also react with oxygen, and in t

13、he case of lipids may initiate chain reactions.Direct effectIR + RH R+HBoth Hand Rradicals can react with another molecule e.g. DNA, lipids, proteins.R+ RH R+ RHRadicals can produce cross linking reactions.R+ R R - R*It is estimated that about one third of biological damage by radiation is caused by

14、 direct effects. *This process becomes more dominant with high LET radiation, such as neutrons or particles.Direct effectThe direct effect of ionizing radiation on DNA molecule 直接作用The absorption of energy depends on the abundance of material in the path of the radiation.Water is the most predominan

15、t molecule in living organisms (about 80 % of the mass of a living cell is water). Therefore, a major proportion of radiation energy deposited will beabsorbed in cellular water. A complex series of chemical changes occurs in water after exposure to ionizing radiation. This process is called water ra

16、diolysis (辐射分解或放射分解). Indirect effect Water radiolysisInteraction of radiation with water causes ionization and excitation process producing short lived H2O+ radical-cations, fast electrons, electronically-excited water molecules (H2O+).H2O+ ions and excited water molecules are unstable and decompos

17、e within 10-13 s to form OH and H radicalsIR + H2O H2O+ + e-H2O + H2O+ H3O+ +OHIR + H2O H2O*H2O +photon emitted or H2O*OH + HWater radiolysisIndirect effect of ionizing radiation on DNA molecules the main factors to affect the effect of ionizing radiation （一）the factors associated to radiation1.type

18、2.dose3.Dose rate4. Fractionated irradiation 5.Area, sites and mode of exposure(二）factors associated with organism1.Radiosensitivity of biological species 2.Radiosensitivity to Individual development 3.Radiosensitivity of tissue and cell4.Radiosensitivity of biological moleculeFactors related to rad

19、iation （一）Type of radiation alpha-particle 、 -partical 、 -RayType of radiation range/air(m) ion pair/mm path alpha-particle 0.01 6000-partical 1 60-Ray 100 0.6（二）Radiation DoseLaw: the effect is more remarkable following theradiation dose increases, but it is not all linear relationship。Median letha

20、l dose （LD50）：the dose to cause 50% mortality for irradiated organisms (L50/60:3-4Gy)LD50/30：radiation dose to cause 50% of the death within 30 days for irradiated organisms. （三）Dose rate (剂量率)Dose rate means amount of absorbed dose per unit time Generally, the biological effect is getting more rema

21、rkable following the radiation dose increases5-50mGy/per day（chronic radiation injury）；50-100mGy/per min（acute radiation injury）（四）Fractionated irradiation (分次照射)-Fractionated irradiation is to reduce biologicaleffects of radiation -For the same dose of radiation, the biological effects from fractio

22、nated irradiation will be weaker than a given effect. -If the dose is more fractionated, and each timeinterval is more longer, which biological effects are getting more smaller because of DNA repair -10Gy/whole body/per time100% mortality of mouse death-10Gy/20 times of fractionation30% mortality of

23、 mouse death（五）Irradiated sites (照射部位) When the irradiation dose and dose rate are the same , the consequences of the whole body from abdominal irradiation is the most serious, then followed pelvis, neck, chest and limbs. （六）Irradiated area (照射面积)irradiated area is more larger, then the biological e

24、ffects are more remarkable as other radiation conditions are the same.（七）Exposure mode (照射方式)Exposure mode include internal, external and mixed exposure. External exposure can divided into uni-directional or multi-directional irradiation, and the biological effects from multidirectional irradiation

25、are more serious than unidirectionalthe factors related to body (与机体有关的因素)Radiosensitivity: when everything about exposure conditions is exactly the same, organism, tissue, or organ differently respond to intensity and speed of radiation: （一） Radiosensitivity of biological species to radiation (生物种系

26、的放射敏感性) The general trend: higher germline evolution and more complex of tissues structure-higher radiosensitivity.Microbial lethal dose was significantly higher than in mammals thousand foldDifferent strains of the same animals has different radiosensitivity（二）Radiosensitivity to Individual develop

27、ment (个体发育的放射敏感性)-Generally, Radiosensitivity is getting decreased following individual development Embryo ：-The pre implantation: Exposed maternal-Embryonic mortality: Pregnancy of people -09th day，Pregnancy of mouse-05th day.-Organogenesis: suffered exposure-congenital malformation: for people-942

28、nd day; mouse-513th day.-Post-Organogenesis: Individual radiosensitivity is getting decreased, but the dysfunction of the central nervous system often occursMicrocephaly(小头畸形), Mental retardation(智力发育迟缓等）。After birth (出生后)：-Childhood to radiation is more sensitive than adult; -The elderly to radiati

29、on is more sensitive than adult because of multiple function decline for elderly. -long term effect, the increase of risk to have aplastic anemia and other cancer for childhood during embryo exposed to radiationChernobyl () nuclear accident(三) Radiosensitivity of different tissues and cellsMore radi

30、osensitive cells: Cells that have a high division rateCells that have a high metabolic rateCells that are of a non-specialized typeCells that are well nourished Sensitivity Cell Cycle PhaseCells are most sensitive to radiation during mitosis (M phase) and RNA synthesis (G2 phase) Less sensitive duri

31、ng the preparatory period for DNA synthesis (G1 phase) Least sensitive during DNA synthesis (S phase) During mitosis (M), the metaphase is the most sensitivityRadioresistant cellsBone LiverKidneyCartilageMuscleNervous tissueRadiosensitive cellsGerminal cellsLymphoid tissues basal cells Hematopoietic

32、 tissuesEpithelium of the GI tractGonads are very radiosensitive FemalesTemporally sterility 1.5 Gy (150 rad)Permanent sterility 5 Gy (500 rad) MalesTemporally sterility 2.5 Gy (250 rad)Permanent sterility 6 Gy (600 rad)Pregnancy and minorsChildren could be expected to be more radiosensitive than ad

33、ultsfetuses more radiosensitive than children and embryos even more in the first weeks of pregnancy when organs are formingRadiosensitivity of various cell typesRadiosensitivity Cell type Low nerve cell muscle cellsIntermediate osteoblast, endothelial cells, fibroblast, spermatids spermatogonia, lym

34、phocytes, stem cells, High intestinal mucosa cells and erythroblast(四) Radiosensitivity of biolofical molecules (亚细胞和分子水平的敏感性)-DNAmRNArRNA and rRNAproteins -RNA and proteins are synthesized during whole cell cycle-DNA is only synthesized at S phase, so its amount is very limited.Biochemical Effect o

35、f ionizing radiationDNA damage and repair mutagens. Radiation lesions in DNA the effect of radiation on DNAChromosome Aberrations-caused by ionizing radiation The type of DNA lesionsRadiation causes a wide range of lesions in DNA ：single strand breaks （SSB）in the phosphodiester linkage,double strand

36、 breaks （DSB）on opposing sites or displaced, base damage,DNA-DNA crossliinksprotein-DNA crosslinks protein-protein crosslinks involving nuclear proteins such as histones and non-histone proteins. The number of DNA lesions generated by irradiation is large, but the number giving rise to cell kill is

37、extremely small. The numbers of lesions induced in the DNA of a cell by a dose of 1-2 Gy are approximately:base damages 1000; single strand breaks (ssb) 1000; double strand breaks (dsb) 40. Broken DNARepair incorrectly Tumour Repair correctlyCells deathCell Survival no repairCell fateThe repair for

38、single strand breaks Base excision repair (BER)Nucleotide excision repair (NER)Mismatch repair (MMR),1.ubiquitous mechanism- Repair a wide variety of lesion 2. essentially error-freeThe repair for double strand breaksNon-homologous end joining (NHEJ)Homologous Recombination (HR)DNA damage repairBase

39、 excision repair （BER）(removing Uracil from DNA)AP sitewhich repairs damage to a single base caused by oxidation, alkylation, hydrolysis, or deamination. The damaged base is removed by a DNA glycosylase. The missing tooth is then recognized by an enzyme called AP endonuclease, which cuts the phospho

40、diester bond. The missing part is then resynthesized by a DNA polymerase, and a DNA ligase performs the final nick-sealing step.Nucleotide excision repair（NER） （ E. coli UvrABC endonuclease）Excinuclease （UvrABC）NickNickDNA polymerase IDNA ligaseExcision endonuclease，a nuclease (enzyme) which excises

41、 a fragment of nucleotides during DNA repair 12-13ntdamage recognitionXPC-hHR23, XPAXPB, XPDXPFERCC1, XPGunwindingnickingrepair synthesisNERin eukaryotesXPA binds the lesionXPA, which encodes a protein that binds the damaged site and helps assemble the other proteins needed for NER. XPB and XPD, whi

42、ch are part of TFIIH. Some mutations in XPB and XPD also produce signs of premature aging. XPF, which cuts the backbone on the 5 side of the damage XPG, which cuts the backbone on the 3 side. Mismatch repair (MMR), which corrects errors of DNA replication and recombination that result in mispaired (

43、but undamaged) nucleotides.Xeroderma Pigmentosum (XP，着色性干皮病 ) : rare autosomal recessive disorder- extreme sensitivity to DNA-damaging agents, particularly UV radiation- skin cancer at a young age- cells defective in NER- neurological disordersThe repair for DNA double strand breaks There are two me

44、chanisms by which the cell attempts to repair a complete break in a DNA molecule: Direct joining of the broken ends. This requires proteins that recognize and bind to the exposed ends and bring them together for ligating. They would prefer to see some complementary nucleotides but can proceed withou

45、t them so this type of joining is also called Nonhomologous End-Joining (NHEJ). Homologous Recombination. Here the broken ends are repaired using the information on the intact Non-Homologous End JoiningModel for the homologous recombination (HR)DNA resectionRad51 filamentStrand invasion Repair synth

46、esisMigrationHoliday junction resolutionMain stepsproteinsMRN/CTIPRad51 Rad52/BRCA2/Rad51paralogRad54 DNA polymeraseXRCC3/ Rad51CHomologous recombination (Error free, S/G2 phase)5 33 5Ionizing Radiation (IR)RPA loadingCell Effect of Ionizing Radiation-Radiological effect of ionizing radiation on cel

47、lular membrane-Radiological effect of ionizing radiation on cell-Radiation induced-chromosome aberrationsCell at Cell Cycle PhaseRadiological Effect Kill cells:During mitosis (M), the metaphase is the most sensitivityPathological changes in cells caused by radiation:-Nucleus change -chromosome aberr

48、ations -membrane change-disassociation between cellular division and proliferation Aneuploidies also detected in these B-R- cells although exact characterization of aneuploidies was not done because SKY karyotyping was not performed on these cells.Bridge with a telomere signal ie. Telomere fusion re

49、sulting dicentric causing this segregation defect manifestationDouble-nucleus or multiple-nucleus caused by radiationChromosome Aberrations-caused by radiationCell cycle arrestHR（S、G2）NHR（whole cell cycle）G1 checkpointG1/S checkpointS checkpointS/G2 checkpointThe damage signaling pathway for keeping

50、 genomic stability Cell Cycle checkpoint activationApoptosisDNA repair(HR, NHR)Telomere maintenanceSensorsDSBs detectionTrigger DNA damage responseMediatorsDSBs signal amplificationDNA DamageEffects(Chk2，BRCA1 ) (BRCA2, Rad51) Genomic stability Radiation-induced chromosome aberrations-Radiation-indu

51、ced chromosome aberrations for living body-Dose-response relationship of chromosome aberrations induced by radiation-biological significance of chromosome aberrations Radiation-induced chromosome aberrations for living body-the effect of radiation on chromosomechromosome aberration chromatid aberrat

52、ion-the effect of radiation on chromosomeChromosome breaks Chromomatid breaks -Dose-effect relationship of chromosome aberrations induced by radiationThe frequency of chromosome aberrations increases with radiation dose to the cells and serves as an indicator of radiation dose received, i.e., a biol

53、ogical dosimeter. In vitro irradiation experiments using blood lymphocytes can provide a dose-response relationship that can be used to estimate radiation dose to individuals on the basis of the aberration frequency detected in their lymphocytes.Relationship between fraction of cells with chromosome

54、 aberrations andradiation dose to AHS survivors exposed in typical Japanese houses Biological significance of chromosome aberrationsGerm cells with chromosome aberrations (such as deletion, mutation or insertions )-higher incident of abortion and stillbirth - incident of abortion, stillbirth and con

55、genital malformations to the descendants of radiation workers is much higher that that of other medical workers Somatic cells with chromosome aberrations-diseases such as immune defect, metabolic defect, shortened life expectancy and tumor. 一、 the effect of ionizing radiation on hemopoietic and bloo

56、d system 电离辐射对造血和血液系统的作用Damage effects of ionizing radiation on the blood system is paid much attention: -Hematopoietic tissue is highly sensitive to radiation tissue. After irradiation，blood system soon have a very significant change in form, function and quantity.-Clinical classification diagnosis

57、 is depends on changes in blood system-the clinical course and prognosis at the its extent and phase are closely related to changes in blood -One of the key measures for clinical treatment is to reduce hematopoietic system damage and promote hematopoietic reconstitution -One late effect of the radia

58、tion is manifested as hematological abnormalities - anemia, leukemia. Hematopoietic organ（造血器官）：-Bone marrow（骨髓）：red-bone marrow, and yellow-bone marrow-lymph node（淋巴结）: lymphocytes-spleen（脾脏）: erythroid cells (occur short time before birth), granulocyte cells (occur before birth) and lymphocytes -l

59、iver（肝脏）: mainly generate the erythroid cells , then granulocyte cellsHematopoietic system Hemopoietic stem cell (造血干细胞)：Poorly differentiated cells (低分化细胞)；mainly distributed in hematopoietic tissue, fewer in peripheral blood (1%)；(2) multiple differentiation potential (具有多向分化潜能)under the appropria

60、te circumstances ，which can differentiateinto various types of mature blood cells, then to be blood cells.(3) self-renewal capacity (具有自我更新能力): the produced offspring is the same as parental hematopoietic stem cells (4) 90 of cells at G0 phase with strong proliferative potential.Hematopoietic system