Heriditary effects of Radiation kmio


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Heriditary effects of Radiation kmio

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Heriditary effects of Radiation kmio

  1. 1. Hereditary Effects of Radiation <ul><li>Presented by: </li></ul><ul><li>DR. SANDESH RAO B </li></ul><ul><li>on 03/08/2011 KMIO Auditorium </li></ul><ul><li>1yr MD(Radiation Oncology Student) </li></ul><ul><li>MODERATOR: </li></ul><ul><li>Dr. Lokesh Viswanath M.D </li></ul><ul><li>Professor & Head of Unit II, Dept of Radiation Oncology </li></ul><ul><ul><li>Kidwai Memorial Institute of Oncology, Bangalore </li></ul></ul>
  2. 2. GENETICS <ul><li>1944 – Avery, MacCleod, Mc Carty </li></ul><ul><li> - DNA – Heriditary material </li></ul><ul><li>Watson & Crick – Double helix </li></ul><ul><li>1956 – Tjio, Levan </li></ul><ul><li> - Ford, Hamerton </li></ul><ul><li> - 46 chromosomes </li></ul>
  3. 3. CHROMOSOMES <ul><li>Long thread like structures – DNA </li></ul><ul><li>Carry all the information that specifies a particular human with all his/her individual characteristics. </li></ul><ul><li>22 pairs of autosomes + 1 pair of allosomes. </li></ul>
  4. 4. DNA <ul><li>Double helix </li></ul><ul><li>Sugar phosphate backbone </li></ul><ul><li>Organic bases – A T C G </li></ul>
  5. 5. <ul><li>Gene – Finite segment of DNA specified by an exact sequence of bases. </li></ul><ul><li>Locus – Position of a gene </li></ul><ul><li>Human genome – DNA of chromosomes + DNA of mitochondria. </li></ul><ul><li>6 billion base pairs of DNA. </li></ul><ul><li>Total no of genes – 50,000 to 1,00,000/haploid set of chromosomes. </li></ul>
  6. 6. MUTATION <ul><li>Any change in chromosomes, their genes, and their DNA. </li></ul><ul><li>Include an array of changes in DNA, such as deletion, rearrangement, breakage in the sugar-phosphate backbone, and base alterations. </li></ul>
  7. 7. Hereditary Effects of Radiation <ul><li>Adverse health effects in descendants due to mutations induced in germ cells. </li></ul><ul><li>Radiation does not produce new unique mutations, but increases the incidence of the same mutations that occur spontaneously. </li></ul><ul><li>Stochastic effect </li></ul><ul><li>Information on the genetic effects of radiation comes almost entirely from animal experiments. </li></ul>
  8. 9. Mendelian Inheritance <ul><li>Autosomal dominant </li></ul><ul><li>Autosomal recessive </li></ul><ul><li>X-linked </li></ul>
  9. 10. Autosomal dominant <ul><li>Expressed in the first generation after its occurrence. </li></ul><ul><li>Polydactyly, achondroplasia, Marfan’s syndrome and Huntington's chorea. </li></ul>
  10. 11. Autosomal recessive <ul><li>Require that the gene be present in duplicate to produce the trait </li></ul><ul><li>Mutant gene must be inherited from each parent </li></ul><ul><li>Sickle-cell anemia, cystic fibrosis, and Tay-Sachs disease. </li></ul>
  11. 12. X-linked <ul><li>Mutations in genes located on the X-chromosome. </li></ul><ul><li>Hemophilia, color blindness, and a severe form of muscular dystrophy </li></ul>
  12. 13. <ul><li>67% are caused predominantly by point mutations (base-pair changes in the DNA) </li></ul><ul><li>22% by both point mutations and DNA deletions within genes (i.e., they are intragenic) </li></ul><ul><li>13% by intragenic deletions and large multilocus deletions. </li></ul>
  13. 14. Chromosomal Changes <ul><li>Abnormalities either in the structure of the chromosomes or in the number of chromosomes </li></ul><ul><li>Down's syndrome </li></ul><ul><li>40% of the spontaneous abortions </li></ul><ul><li>6% of stillbirths </li></ul><ul><li>Radiation is much more effective at breaking chromosomes than in causing errors in chromosome distribution. </li></ul>
  14. 15. <ul><li>Irradiation induces a dose dependent delay in the entry of cells into mitosis & when cells that were irradiated while in interphase begins to divide some of reveal chromosome aberrations. </li></ul><ul><ul><li>Chromosome aberrations </li></ul></ul><ul><ul><li>Chromatid aberrations </li></ul></ul>
  15. 19. Multifactorial <ul><li>Known to have a genetic component </li></ul><ul><li>Transmission pattern not simple Mendelian </li></ul><ul><li>Congenital abnormalities: cleft lip with or without cleft palate; neural tube defects </li></ul><ul><li>Adult onset: diabetes, essential hypertension, coronary heart disease </li></ul><ul><li>Interaction with environmental factors </li></ul>
  16. 21. RADIATION-INDUCED HEREDITARY EFFECTS IN FRUIT FLIES <ul><li>1927 – Müller - exposure to x-rays could cause readily observable mutations in the fruit fly, Drosophila melanogaster . </li></ul><ul><li>Included a change of eye color from red to white, the ebony mutant with its jet-black color, the “vestigial wing” mutant, and the recessive lethal mutation. </li></ul>
  17. 22. <ul><li>Hereditary changes were considered the principal hazard of exposure to ionizing radiation because </li></ul><ul><ul><li>A low doubling dose (5-150 R) for mutations </li></ul></ul><ul><ul><li>Hereditary effects were cumulative </li></ul></ul><ul><ul><li>Little was known of the carcinogenic potential of low doses of radiation. </li></ul></ul>
  18. 23. RADIATION-INDUCED HEREDITARY EFFECTS IN MICE <ul><li>Russell and Russell - Oak Ridge National Laboratory </li></ul><ul><li>To determine specific locus mutation rates in the mouse </li></ul><ul><li>Megamouse project - 7 million mice </li></ul><ul><li>An inbred mouse strain was chosen in which seven specific mutations occur, 6 involving change of coat color & 1 as stunted ear. </li></ul>
  19. 25. <ul><li>Five major conclusions </li></ul><ul><li>The radiosensitivity of different mutations varies by a significant factor of about 35 </li></ul><ul><li>Dose rate effect was evident. </li></ul><ul><ul><li>Chronic dose exposure induces fewer mutations </li></ul></ul><ul><ul><li>Acute dose exposure induces more mutation </li></ul></ul><ul><ul><li>This is in contrast with Drosophila </li></ul></ul><ul><li>The male is more radiosensitive than females. </li></ul><ul><li>The genetic effects of a given radiation dose can be reduced greatly if a time interval is allowed between exposure and conception. </li></ul><ul><li>The estimate of the doubling dose adopted by BEIR V and UNSCEAR 88 is 1 Gy. </li></ul>
  20. 27. RADIATION-INDUCED HEREDITARY EFFECTS IN HUMANS <ul><li>Two basic pieces of data are needed: </li></ul><ul><ul><li>Base-line spontaneous mutation rate in humans – 738,000 per million. </li></ul></ul><ul><ul><li>The doubling dose (1 Gy, or 100 rad). </li></ul></ul>
  21. 28. Two Correction Factors <ul><li>Not all mutations lead to disease. </li></ul><ul><li>The mutation component (MC): </li></ul><ul><ul><li>0.3 for autosomal dominant. </li></ul></ul><ul><ul><li>0.0 for autosomal recessive. </li></ul></ul><ul><ul><li>0.01-0.02 for chronic multifactorial. </li></ul></ul><ul><li>The 7 specific locus mouse mutations are not representative; they are genes not essential for viability. Only a small proportion of human genes, when mutated, would result in live births. </li></ul>
  22. 30. Hereditary Effects − ICRP <ul><li>Total population 0.2%/Sv </li></ul><ul><li>Working population 0.1%/Sv </li></ul><ul><li>Based on: </li></ul><ul><ul><li>Hereditary risks for first two generations. </li></ul></ul><ul><ul><li>Life expectancy 75 yrs; reproductive age 30 yrs. </li></ul></ul><ul><ul><li>Total population 30/75 of reproductive pop. </li></ul></ul><ul><ul><li>Working population 30–18/70 of reproductive pop. </li></ul></ul>
  23. 31. Hereditary Effects of Radiation - Human <ul><li>Children of the survivors of Hiroshima and Nagasaki have been studied for untoward pregnancy outcomes, death of live-born children, sex chromosome abnormalities, electrophoretic variants of blood proteins. </li></ul><ul><li>Though no genetic indication is statistically significant, the average doubling dose is 156 rem (1.56 Sv). </li></ul>
  25. 33. References <ul><li>Radiobiology for the Radiologist – Hall, Eric J.; Giaccia, Amato J. </li></ul><ul><li>Basic clinical Radiobiology – Gordon Steel </li></ul><ul><li>Radiation Biology – Donald Pizzarello </li></ul><ul><li>Clinical Radiobiology – Duncan, Nias </li></ul><ul><li>Clinical genetics – Laird G. Jackson, R. Neil Schimke. </li></ul>
  26. 34. <ul><li>THANK YOU </li></ul>
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