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HERITABLE EFFECTS OF RADIATION By Dr.Ayush Garg

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HERITABLE EFFECTS OF RADIATION

HERITABLE EFFECTS OF RADIATIONByDr.Ayush Garg

GERM CELL PRODUCTION AND RADIATION EFFECTS ON FERTILITY

BASICS OF GENETICSCHROMOSOME

Contains long threadlike structures called DNACarries all the information that specifies a particular human with his/her individual characteristics22 pair of autosomes + 1 pair of allosomes

DNA

Double helix

Organic bases

Sugar-phosphate backbone

Gene Finite segment of DNA specified by an exact sequence of bases.Locus Position of a geneHuman genome DNA of chromosomes + DNA of mitochondria.6 billion base pairs of DNA.Total no of protein encoding genes 25,000 to 50000/haploid set of chromosomes.

MUTATIONAny 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.

HERITABLE EFFECTS OF RADIATIONAdverse 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.Information on the genetic effects of radiation comes almost entirely from animal experiments.

HERITABLE DISEASES

MENDELIAN INHERITANCEAutosomal DominantAutosomal RecessiveX-linkedMendelian Diseases

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Autosomal DominantExpressed in the first generation after its occurrence.

Egs - Polydactyly, achondroplasia, Marfans syndrome and Huntington's chorea.

Autosomal RecessiveRequire that the gene be present in duplicate to produce the traitMutant gene must be inherited from each parentEgs - Sickle-cell anemia, cystic fibrosis, and Tay-Sachs disease.

X-LinkedMutations in genes located on the X-chromosome.

Egs - 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 CHANGESAbnormalities either in the structure of the chromosomes or in the number of chromosomesDown's syndrome40% of the spontaneous abortions6% of stillbirthsRadiation is much more effective at breaking chromosomes than in causing errors in chromosome distribution.

MULTIFACTORIALKnown to have a genetic componentTransmission pattern not simple MendelianCongenital abnormalities: cleft lip with or without cleft palate; neural tube defectsAdult onset: diabetes, essential hypertension, coronary heart diseaseInteraction with environmental factors

RADIATION-INDUCED HEREDITARY EFFECTS IN FRUIT FLIES1927 Mller - 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 becauseA low doubling dose (5-150 R) for mutationsHereditary effects were cumulativeLittle was known of the carcinogenic potential of low doses of radiation.The doubling dose is the dose required to double the spontaneous mutation rate.

RADIATION-INDUCED HEREDITARY EFFECTS IN MICERussell and Russell - Oak Ridge National LaboratoryTo determine specific locus mutation rates in the mouseMegamouse project - 7 million miceAn inbred mouse strain was chosen in which seven specific mutations occur, 6 involving change of coat color & 1 as stunted ear.

Five major conclusionsThe radiosensitivity of different mutations varies by a significant factor of about 35Dose rate effect was evident.Chronic dose exposure induces fewer mutationsAcute dose exposure induces more mutationThis is in contrast with DrosophilaThe oocytes are exquisitely radiosensitive.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.

Committee on the Biological Effects of Ionizing Radiation (BEIR V)United Nations Scientifi c Committee on the Effects of Atomic Radiation (UNSCEAR23

RADIATION-INDUCED HEREDITARY EFFECTS IN HUMANSTwo basic pieces of data are needed:Base-line spontaneous mutation rate in humans 738,000 per million.Doubling Dose (1 Gy, or 100 rad).

RADIATION AND SEX CELLSResistantPost-spermatogonial cellsSensitiveStem cellsTemporary sterility15 rad (0.15 Gy)40 rad/year (0.4 Gy/yr)Permanent sterility350-600 rad (3.5 to 6 Gy)200 rad/yr (2 Gy/yr)No significant hormonal imbalanceResistantPost-oogonial cellsSensitivefolliclesPermanent sterility250-600 rad (2.5 to 6 Gy)20 rad/yr (0.2 Gy/yr)

Pronounced hormonal imbalanceMalesFemales

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Two Correction FactorsNot 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.

Assuming an average life expectancy of 75 years, with mean reproductive age stopping at 30 yearsThe risk coefficients for a total population of all ages will be 30/75, that is, 40% of that for a reproductive population. This rounds out at 0.2% per sievert. For a working population, the age range is only from 18 to 30 years because of the fact that no one is allowed to be a radiation worker before the age of 18 and the reproductive cycle is assumed to end at the age of 30Consequently, the risk coefficients will be 12/75, or 16% of that for a reproductive population, which rounds out at 0.1% per sievert.

Hereditary Effects of Radiation - HumanChildren 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

CHANGING CONCERNS FOR RISKSDose limit of radiation workers reduced to 50mSv per year(by ICRP in 1956)The level of concern regarding genetic effects has declined steadily as a consequence the percentage of radiation detriment attributed to the genetic component in view of ICRP has declined from 100% in 1955 to 4% in 2007The level of concern involving radiation carcinogenesis has increased as more and more solid tumours have appeared in the Japanese A-bomb survivors

EPIGENETICSChanges in gene expression that takes place without a change in the DNA sequenceThe changes result from mainly these molecular modifications - DNA methylation which takes place at the carbon 5 position of cytosine in CpG dinucleotides - Changes to chromatin packaging of DNA by post translational histone modifications

Pre natal and early postnatal environmental factors can result in altered epigenetic programming and subsequent changes in the risk of developing disease later in life

Environmental changes studied include nutritional supplements, xenobiotic chemicals and exposure to ionizing radiation

Radiation studies showed that exposure of adult mice led to transgenerational genome instability in the offspring resulting from a significant loss of DNA methylation in somatic tissue.In addition there is some evidence from animal studies that epigenetic alterations may be inherited trans- generationally thereby affecting the health of future generations

IMPRINTED GENES

Expression is from only one parental allele with the other allele silenced this leads to a non mendelian germ line inherited form of gene regulation that involves heritable DNA methylation and histone modificationExpression of an imprinted gene in the present generation depends on the environment that it experienced in the previous generation

EFFECTS OF RADIATION ON THEEMBRYO AND FETUS

Commonly used measurements for ionizing radiation and their units

(Nuclear Wastelands, Makhijani et al., eds., Cambridge: MIT Press, 1995)UnitsDescriptionequivalentRem(roentgen equivalent man)A unit of equivalent absorbed dose of radiation with relative biological effectivenessrem = rad x QSievert (Sv)A unit of equivalent absorbed dose equal to 100 rem.1 Sv = 100 remSv = Gy x QRad(radiation absorbed dose)A unit of absorbed dose of radiation. Rad is a measure of the amount of energy deposited in tissue1 rad = 100erg/gramGray (Gy)A unit of absorbed radiation dose equal to 100 rad. Gray is a measure of deposition of energy in tissue1 Gy = 100 rad

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Health impact of high-dose radiation from a nuclear disasterCell deathAlter DNA of normal cellsUncontrolled cell divisionsInduce cancerDamage organsAcute radiation sickness (coagulopathy, immunity disorders)DiarrheaFever, burns, coordination & equilibrium disturbances

Ionizing radiation from Natural source

40 , , , 40

Ionizing radiation from Natural source

(World Nuclear Association)

41 , , , 41

Effects of Prenatal RadiationExposure

Effects of radiation in pregnancyPregnancy lossMalformationNeurobehavioral abnormalitiesFetal growth restriction --- deterministic effect --- Threshold or NOAEL (No-Adverse-Effect Level)

Cancer --- Stochastic effect --- More radiation, greater the chance of the disease --- No defined threshold

Effects of radiation in pregnancy- Deterministic effectRadiation dose, the trimester of the pregnancy

Ex) Pregnancy lossDuring the 1st 2 weeks after conception, 100-200mGy (10-20 rad)Shortly thereafter, 250-500 mGy (25-50 rad)18weeks, 5000mGy (500 rad)At term, 20, 000mGy (2000rad)

EffectMost sensitive period after conception(d)Threshold dose at effect was observed (mGy)Absolute incidenceAnimal studiesHuman studiesPerinatal death Preimplantation Postimplantation0-850-100 250NDNDGrowth retardation8-5610200NDOrgan malformation14-56250250NDSmall head size14-105100No threshold observed0.05-0.1%Severe mental retardation56-105ND1000.04%Reduction of IQ56-105ND100NDChildhood cancer0-77No thresholdNo threshold0.017%

Fetal Effects from Low-level Radiation Exposure(Wagner LK, 1997)

45 . 2 . 8-15 mental retardation, IQ . 16-25 8-15 . .

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Radiation and mental retardation8-15 weeks, : Risk of impaired CNS development > 5 times than 16~25 weeks

< 8 weeks, or > 25 weeksNo increased risk of mental retardation

OVERVIEW OF RADIATION EFFECTSON THE EMBRYO AND FETUSLethal EffectsMalformationsGrowth disturbances and growth retardation, without malformations

LETHAL EFFECTSThese are induced by radiation before or immediately after implantation of the embryo into the uterine wall or are induced after increasingly higher doses during all stages of intrauterine development, to be expressed either before birth (prenatal death) or at about the time of birth (neonatal death).

MALFORMATIONSThese are characteristic of the period of major organogenesis in which the main body structures are formed, and especially of the most active phase of cell multiplication in the relevant structures.

GROWTH DISTURBANCES AND GROWTH RETARDATION, WITHOUT MALFORMATIONSThese are induced at all stages of development but particularly in the latter part of pregnancy.

The principal factors of importance are the dose and the stage of gestation at which it is delivered.

Russell and Russell divided the total developmental period in utero into three stages:

Preimplantation

Organogenesis

EXPERIENCE IN HUMANS

Survivors of the A-Bomb Attacks onHiroshima and Nagasaki Irradiated In Utero

Exposure to Medical RadiationDekaban surveyed the literature for instances of pelvic x-irradiation in pregnant women. Based on the available data, the following generalizations were proposed:1. Large doses of radiation (2.5 Gy) delivered to the human embryo before 2 to 3 weeks of gestation are not likely to produce severe abnormalities in most children born, although a considerable number of the embryos may be resorbed or aborted.

2.Irradiation between 4 and 11 weeks of gestation would lead to severe abnormalities of many organs in most children.

3.Irradiation between 11 and 16 weeks of gestation may produce a few eye, skeletal, and genital organ abnormalities; stunted growth, microcephaly, and mental retardation are frequently present.

4. Irradiation of the fetus between 16 and 25 weeks of gestation may lead to a mild degree of microcephaly, mental retardation, and stunting of growth.

5. Irradiation after 30 weeks of gestation is not likely to produce gross structural abnormalities leading to a serious handicap in early life but could cause functional disabilities.

COMPARISON OF HUMAN ANDANIMAL DATA

63Fetal Radiation RiskThere are radiation-related risks throughout pregnancy which are related to the stage of pregnancy and absorbed doseRadiation risks are most significant during organogenesis and in the early fetal period somewhat less in the 2nd trimester and least in the third trimester

LessLeastMost risk

This table summarizes the lowest doses atwhich effects on the embryo and fetus havebeen observed.

CANCER IN CHILDHOOD AFTER IRRADIATION IN UTERO

The Oxford Survey of Childhood Cancers, published by Stewart and Kneale in the 1950s, suggested an association between the risk of cancer, principally leukemia, up to 15 years of age and exposure inutero to diagnostic x-rays. This was a retrospective case-controlled study and is summarized in this table

Radiation exposure on infants and lactating women Direct exposure to radiation on breastIngestion of radioactive pharmaceuticals

Mammogram ---- breastfeeding (O)

The highest radiation conc. in breast milk3-4 hours after adm. of radioactive pharmaceuticalsradiation absorbed by fetus < 3-10% of the total dose absorbed by a womanBut, no negligible dose !1 Gy in infant :thyroid cancer(x10)

CDC: if radioactive iodine ----stop breastfeeding !

Protection of pregnant women and fetuses from radiation exposureMaintaining a safe distanceShielding ones body from exposureAvoiding ingestion of food and water contaminated with radioactive particles in the air, rain, or soil

In disaster, minimize the exposureLead-containing vestIn radioactive pharmaceuticals, hydration + voiding!

If safe protocol, < 1mSv /year

Probability of birth with no malformation and no childhood cancerDose to conceptus (mGy)No malformation (%)No childhood cancer(%)No malformation and No childhood cancer (%)096.0099.9395.930.595.99999.92695.9281.095.99899.92195.9222.595.99599.90895.915.095.9999.8995.8810.095.9899.8495.8350.095.9099.5195.43100.095.8099.0794.91

(Wagner LK et al. 1982)

ThusICRP (The International Commission on Radiological Protection) < 100mGy (10 rad) : Not medical ground for termination

ACOG Threshold for medical concern ~ 50mGy (5 rad)> 1000mGy (100 rad) : Serious risk to fetus CNS---severe mental retardationSingle diagnostic radiation exposure? 10rad? 5 rad?

70Research on Pregnant PatientsRadiation research involving pregnant patients should be discouraged

THANK YOU