1. Ahmed Group Lecture 27 Hereditary Effects of Radiation Lecture 27

2. Ahmed Group Lecture 27 Single gene mutation Chromosome aberrations Relative vs. absolute mutation risk Doubling dose Heritable effects in humans Risk estimates for hereditable effects

3. Ahmed Group Lecture 27 Genetic diseases are attributed to mutations occurring in germ cells and are transmitted to progeny (hereditary diseases). Spontaneous mutation rates are increased by radiation exposure Three principal categories of genetic diseases: Mendelian Chromosomal Multifactorial

4. Ahmed Group Lecture 27 Mendelian Inheritance Autosomal dominant Autosomal recessive X-linked Mendelian Diseases

5. Ahmed Group Lecture 27 Chromosomes Homologous Heterologous Homozygous Heterozygous

6. Ahmed Group Lecture 27 Process of Division Somatic Cells Germinal Cells Mitosis Meiosis

7. Ahmed Group Lecture 27 Cell Division and Chromosome Number in Sex Cells

8. Ahmed Group Lecture 27 Spermatogenesis Spermatogonia Primary spermatocytes Secondary spermatocytes Spermatids Spermatozoa Germ cell production in the male mammals

9. Ahmed Group Lecture 27 Oogenesis Oogonia Primary oocyte Secondary oocyte Ootids Oocyte Germ cell production in the female mammals

10. Ahmed Group Lecture 27 Chromosome Number

11. Ahmed Group Lecture 27 Chromosomal aberrations Gross abnormalities either in structure or number of chromosomes such as Robertsonian translocation, monosomy, trisomy and deletion. Multifactorial diseases Diseases known to have genetic component but also environmental factors: -Known to have a genetic component -Transmission pattern not simple Mendelian -Congenital abnormalities: cleft lip with or without cleft palate; neural tube defects -Adult onset: diabetes, essential hypertension, coronary heart disease -Interaction with environmental factors

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14. Ahmed Group Lecture 27 Single gene mutation Chromosome aberrations Relative vs. absolute mutation risk Doubling dose Heritable effects in humans Risk estimates for hereditable effects

15. Ahmed Group Lecture 27 Radiation induced hereditary effects Children of Japanese survivors of atomic bomb attacks on Hiroshima and Nagasaki. Relative versus direct mutation risk “If nature can do it, radiation can do it”. In a set of genes: Av of spontaneous mutation rate Relative mutation risk = Av of radiation-induced mutation rate

16. Ahmed Group Lecture 27 Megamouse Project 7 million mice were used Five major conclusions 1.The radiosensitivity of different mutations varies by a significant factor of about 35 1.Dose rate effect was evident. Chronic dose exposure induces fewer mutations Acute dose exposure induces more mutation This is in contrast with Drosophila

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19. Ahmed Group Lecture 27 Five major conclusions continued 3.The male is more radiosensitive than females. 4.The genetic effects of a given radiation dose can be reduced greatly if a time interval is allowed between exposure and conception. 5.The estimate of the doubling dose adopted by BEIR V and UNSCEAR 88 is 1 Gy. Megamouse Project

20. Ahmed Group Lecture 27 Single gene mutation Chromosome aberrations Relative vs. absolute mutation risk Doubling dose Heritable effects in humans Risk estimates for hereditable effects

21. Ahmed Group Lecture 27 Doubling Dose The doubling dose is the dose required to double the spontaneous mutation rate. A low doubling dose (5-150 R) for mutations was estimated from fruit fly experiments. Hereditary effects are cumulative. Excess incidence of leukemia was evident but much larger number of solid tumors did not appear until many years later in Japanese survivors of the A-bomb attack.

22. Ahmed Group Lecture 27 Single gene mutation Chromosome aberrations Relative vs. absolute mutation risk Doubling dose Heritable effects in humans Risk estimates for hereditable effects

23. Ahmed Group Lecture 27 Radiation and Sex Cells Resistant –Post-spermatogonial cells Sensitive –Stem cells Temporary sterility –15 rad (0.15 Gy) –40 rad/year (0.4 Gy/yr) Permanent sterility –350-600 rad (3.5 to 6 Gy) –200 rad/yr (2 Gy/yr) No significant hormonal imbalance Resistant –Post-oogonial cells Sensitive –follicles Permanent sterility –250-600 rad (2.5 to 6 Gy) –20 rad/yr (0.2 Gy/yr) Pronounced hormonal imbalance Males Females

24. Ahmed Group Lecture 27 Hereditary effects of radiation in humans

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