Heriditary effects of Radiation kmio

Hereditary Effects of Radiation

Presented by: DR. SANDESH RAO B

on 03/08/2011 KMIO Auditorium1yr MD(Radiation Oncology Student)

MODERATOR: Dr. Lokesh Viswanath M.D

Professor & Head of Unit II, Dept of Radiation OncologyKidwai Memorial Institute of Oncology, Bangalore

GENETICS

• 1944 – Avery, MacCleod, Mc Carty - DNA – Heriditary material

• Watson & Crick – Double helix

• 1956 – Tjio, Levan - Ford, Hamerton - 46 chromosomes

CHROMOSOMES

• Long thread like structures – DNA

• Carry all the information that specifies a particular

human with all his/her individual characteristics.

• 22 pairs of autosomes + 1 pair of allosomes.

DNA

-Double helix

-Sugar phosphate backbone

-Organic bases – A T C G

• Gene – Finite segment of DNA specified by an

exact sequence of bases.

• Locus – Position of a gene

• Human genome – DNA of chromosomes + DNA of

mitochondria.

• 6 billion base pairs of DNA.

• Total no of genes – 50,000 to 1,00,000/haploid

set of chromosomes.

MUTATION

• Any change in chromosomes, their genes, and their DNA.

• Include an array of changes in DNA, such as deletion, rearrangement, breakage in the sugar-phosphate backbone, and base alterations.

Hereditary Effects of Radiation

• Adverse health effects in descendants due to mutations induced in germ cells.

• Radiation does not produce new unique mutations, but increases the incidence of the same mutations that occur spontaneously.

• Stochastic effect• Information on the genetic effects of radiation

comes almost entirely from animal experiments.

Mendelian Inheritance

• Autosomal dominant

• Autosomal recessive

• X-linked

Autosomal dominant

• Expressed in the first generation after its occurrence.

• Polydactyly, achondroplasia, Marfan’s syndrome and Huntington's chorea.

Autosomal recessive

• Require that the gene be present in duplicate to produce the trait

• Mutant gene must be inherited from each parent

• Sickle-cell anemia, cystic fibrosis, and Tay-Sachs disease.

X-linked

• Mutations in genes located on the X-chromosome.

• Hemophilia, color blindness, and a severe form of muscular dystrophy

• 67% are caused predominantly by point mutations (base-pair changes in the DNA)

• 22% by both point mutations and DNA deletions within genes (i.e., they are intragenic)

• 13% by intragenic deletions and large multilocus deletions.

Chromosomal Changes

• Abnormalities either in the structure of the chromosomes or in the number of chromosomes

• Down's syndrome• 40% of the spontaneous abortions• 6% of stillbirths• Radiation is much more effective at breaking

chromosomes than in causing errors in chromosome distribution.

• 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.

–Chromosome aberrations

–Chromatid aberrations

Multifactorial

• 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

RADIATION-INDUCED HEREDITARY EFFECTS IN FRUIT FLIES

• 1927 – Müller - exposure to x-rays could cause readily observable mutations in the fruit fly, Drosophila melanogaster.

• 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.

• Hereditary changes were considered the principal hazard of exposure to ionizing radiation because

– A low doubling dose (5-150 R) for mutations

– Hereditary effects were cumulative

– Little was known of the carcinogenic potential of

low doses of radiation.

RADIATION-INDUCED HEREDITARY EFFECTS IN MICE

• Russell and Russell - Oak Ridge National Laboratory

• To determine specific locus mutation rates in the mouse

• Megamouse project - 7 million mice• An inbred mouse strain was chosen in which

seven specific mutations occur, 6 involving change of coat color & 1 as stunted ear.

• Five major conclusions1. The radiosensitivity of different mutations varies

by a significant factor of about 352. Dose rate effect was evident.– Chronic dose exposure induces fewer mutations– Acute dose exposure induces more mutation– This is in contrast with Drosophila

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.

RADIATION-INDUCED HEREDITARY EFFECTS IN HUMANS

• Two basic pieces of data are needed:–Base-line spontaneous mutation rate in

humans – 738,000 per million.

– The doubling dose (1 Gy, or 100 rad).

Two Correction Factors

• Not all mutations lead to disease.• The mutation component (MC):– 0.3 for autosomal dominant.– 0.0 for autosomal recessive.– 0.01-0.02 for chronic multifactorial.

• 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.

Hereditary Effects − ICRP

• Total population 0.2%/Sv• Working population 0.1%/Sv• Based on:– Hereditary risks for first two generations.– Life expectancy 75 yrs; reproductive age 30 yrs.– Total population 30/75 of reproductive pop.– Working population 30–18/70 of reproductive

pop.

Hereditary Effects of Radiation - Human

• 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.

• Though no genetic indication is statistically significant, the average doubling dose is 156 rem (1.56 Sv).

MUTATIONS IN THE CHILDREN OF THE A-BOMB SURVIVORS

References

• Radiobiology for the Radiologist – Hall, Eric J.; Giaccia, Amato J.

• Basic clinical Radiobiology – Gordon Steel• Radiation Biology – Donald Pizzarello• Clinical Radiobiology – Duncan, Nias• Clinical genetics – Laird G. Jackson, R. Neil

Schimke.

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