Hereditary Effects of Radiation

1. Hereditary Effects of Radiation Lecture 27

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

3. 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. Mendelian Inheritance Mendelian Diseases Autosomal dominant Autosomal recessive X-linked

5. Chromosomes Homologous Heterologous Homozygous Heterozygous

6. Somatic Cells Process of Division Mitosis Germinal Cells Meiosis

7. Cell Division and Chromosome Number in Sex Cells

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

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

10. Chromosome Number

11. 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

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

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

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

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

21. Doubling DoseThe 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. Single gene mutation Chromosome aberrations Relative vs. absolute mutation risk Doubling dose Heritable effects in humans Risk estimates for hereditable effects

23. Radiation and Sex Cells Females Males • 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 • 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

24. Hereditary effects of radiation in humans