I.E. Vorobtsova*


Abstract.
Genetic effects of ionizing radiation in the progeny of exposed parents could be conventionally subdivided on three main types. 1. Severe developmental disorders
(fetus death, stillbirth, early postnatal mortality, malformation, hereditary disease, sterility). These effects are known to be caused by so called «gross» mutations
(genomic, chromosomal, those of essential genes) with dominant harmful effects.
Although found in rodents, insects, fishes they have not been found in humans. The proposal is made that the higher reproductive potency of a species the higher its tolerance for defective organisms. Due to strong selection against severe defects at the earliest stage of pregnancy, this genetic effect of radiation is likely to be difficult to detect in people. 2. Increased cancer risk manifested as elevated incidence of spontaneous tumors and increased sensitivity to carcinogenic agents. 3. Decreased fitness (non-carcinogenic negative health effects). These two last types of radiation genetic effects are presumably due to instability and functional inferiority of cell genome in the progeny of irradiated parents. The genetic background of these effects is suggested to be the load of induced minor mutations in regulatory genes (mini-, microsatelite loci) or /and epigenomic rearrangements of DNA in parental germ cells transmitted to progeny. These radiation genetic effects are much more obvious in animals as compared to humans. Apparently, they are difficult to find in humans because of their essential dependence on promotive (life style) factors, which are impossible to control in the offspring of irradiated people.
A comparison of somatic (in irradiated organisms) and genetic (in the progeny of irradiated parents) effects of radiation provide evidence on the phenomenological as well as pathogenic similarity.
Key words: ionizing radiation, genetic and somatic effects, humans, animals.

The recent knowledge of genetic effects of ionizing radiation in the first generation progeny of irradiated parents permit to subdivide them conventionally on three main types: severe developmental disorders, increased cancer risk and decreased fitness (non-carcinogenic negative health effects).
The most studied genetic effects of radiation are the severe disorders in the progeny of irradiated organisms such as: death of embryos, stillbirth, early postnatal death, congenital abnormality, malformation, hereditary disease, sterility [1]. These serious disorders are known to be caused by so called "gross mutations" (genomic, chromosomal, those of essential genes) with harmful dominant effects. They are expressed unequally in different biological species. Although found in animals they have not so far been identified in humans. The large-scale investigation of atomic bomb survivors in Hiroshima and Nagasaki, found no significant difference between the progeny of irradiated and of non-irradiated parents in the incidence of untoward pregnancy outcome, frequency of hereditary diseases, chromosomal aberrations and mutations. In 1974 Vorobtsova suggested that the expression of severe genetic effects directly depended on the reproductive potency of the species [2, 3]. Humans are characterized by a low reproductive potency (single, long-term gestation), an evolutionary situation that would favor selection against serious hereditary defects at the earliest stages of development. The majority of serious genetic injuries arisen due to radiation are probably eliminated at the germ or early zygotic stages and the pregnancy is interrupted on the prediagnostic period. That is why these genetic effects of radiation are difficult to detect in humans.
The fecundity of rodents is higher (multiple, short-term pregnancy). If the presence of abnormal embryos due to parental irradiation resulted in interruption of

gestation, it would be fatal to the entire litter and would thus reduce sharply the numbers in the next generation. Thus, in spite of the intrauterine death of some fetuses, the gestation progresses, but the frequency of early mortality, malformations, sterility, mutations are higher among the live-born progeny of irradiated animals than in the control. Presence of defective individuals, however, is not dramatic for population because they are not likely to participate in reproducing the next generation due to decreased postnatal survival and sterility.
Insects, fishes produce much more descendants in each subsequent generation than it is needed to maintain a size of the population. A great variety of mutants are known to arise in the progeny of irradiated parents in such species. It provides evidence on the low strength of preimaginal selection against defective individuals.
Thus the higher the reproductive potency of a species the higher its tolerance for the defective organisms and the higher possibility to reveal the genetic effects of parental exposure manifested as severe developmental disorders in the offspring.
Another genetic effect of ionizing irradiation is an increased cancer risk in the progeny of exposed parents. Stewart et al . was the first to reveal an increased incidence of leukemia among children of women who had undergone diagnostic irradiation prior to conception [4]. Epidemiological data concerning this problem have been obtained on the children whose parents were exposed to diagnostic, therapeutic and occupational irradiation or were atomic bomb survivals. These data were not uniform and did not permit to make a definite conclusion on the carcinogenic effect of parental irradiation in human [5].
Less contradictory data have been obtained from experiments [reviewed in ref.
3]. An increased frequency, shortened latency and greater malignancy of spontaneous

tumors in the F
1
were found in progeny of irradiated rodents. Increased carcinogenesis in the progeny of animals incorporated radio nuclides also has been shown. We were the first to show that not only spontaneous blastomogenesis is increased in the progeny of irradiated animals [6]. More pronounced effect of parental exposure is observed if the progeny is undergone the challenge treatment with secondary carcinogenic agent. In fact, the frequency of lung adenomas and other tumors induced by urethane was significantly higher among the offspring of irradiated male mice as compared to control animals treated with urethane [3, 7]. In the 70 th
the concept on the possibility of transmission via germ cells the injuries of DNA caused the predisposition of offspring to carcinogenesis was rather unpopular. In 80 th
the similar data obtained by Nomura [8] attracted the attention of researchers to this genetic effect of radiation. During the last two decades these results were confirmed [9, 10]. It was demonstrated that carcinogenic effect of parental exposure to radiation and chemicals persisted over several generations. This heritable effect was named multigenerational carcinogenesis [reviewed in ref. 3].
What is the genetic mechanism involved in this effect? We proposed that genomic instability arose in the progeny of cells due to paternal irradiation and were the first to obtain data supported this hypothesis [6]. The F1 generation of irradiated male rats and Drosophila manifested the genomic instability as enhanced chromosomal sensitivity to mutagenic factors [11, 12, 13]. The similar data we obtained later for the children born to parents undergone preconception radiation treatment [14] and for children of liquidators of Chernobyl accident consequences
(unpublished data). The problem of transmissible genomic instability induced by parental irradiation is becoming now one of the most intrigues and widely investigated [15] The results of recent studies [reviewed in refs 16,17] which were

performed using another endpoints of genomic instability and modern molecular technology are consistent with the data we obtained in early 70 th .
The human data addressed to this problem are extremely scanty. They were being obtained from 1920 on children born from parents irradiated by medical reasons, occupationally or from atomic bomb survivors. It was concluded that no detrimental health effects were determined in these cohorts. The interest to this problem sharply increased after Chernobyl catastrophe and some data appeared demonstrating negative health effects in children whose parents survived this accidental irradiation [18]. At the same time no health effects were observed in the offspring of parents exposed to occupational irradiation on the plant "Mayak" [19]. It is worth to note that to confirm such effects with confidence many factors which are able to influence the results should be taken into account: the size of cohorts, adequacy of controls, social and life style factors, methods of assessment of health and so on.
Experimental results on the fitness of irradiated parents progeny obtained in 50-60 th were fragmentary and not uniform. In 1957 Russell et al. reported that the progeny of male mice exposed to neutron irradiation had shorter life span than the progeny of intact animals [20]. However, the results of later investigations both in the first generation offspring of irradiated animals (rodents, Drosophila) and in descendants of multi-generation parental exposure have been rather contradictory and difficult to compare [reviewed in ref. 2]. It is likely to be due to variations in experimental design
(type of radiation used for parental exposure, gender of exposed parents, stage of germ cells from which the progeny was derived, estimated endpoint of fitness). The genetic background of experimental animals (inbred, outbreed, hybrid) could as well contribute to variability of results.

During 1965-1980 we performed large-scale experiments on two systematically distant species: Drosophila and rodents to investigate fitness of irradiated parent’s progeny. Uniform experimental design was used. The F
1
generation of exposed parents was studied; the progeny was derived from irradiated mature germ cells of exposed males; the fitness of descendants was estimated using multiple endpoints; the fitness was estimated on cell, tissue and organism levels; various challenges were used to reveal the impaired fitness of animals, which would not be evident without such challenges. The results clearly demonstrated the existence of radiation-induced genetic effects in animals manifesting as decrease fitness in the F
1
generation progeny of irradiated animals. The expression of these effects depended strongly on the genetic background of strain studied, on the nature of the challenge and endpoint chosen. The majority of results obtained have been published in Russian journals in
70-80 th
. The brief description of our results and those of other authors one can find
(see refs. 2, 3, 13). Thus in animal experiments of 60-70 th it was on principle proved that genetic effects of paternal irradiation comprise not only severe developmental disorders in progeny but as well, increased cancer risk and impaired fitness of phenotypic normal descendents. However these findings were too unexpected and incompatible with one of the main dogma of classical genetics confirming full receciveness of newly arisen mutations and at that time were neglected.
The genetic mechanisms leading to such radiation genetic effects as increased cancer risk, genomic instability and impaired fitness are unclear up till now. Various casual factors have been suggested ever and recently: mutations in polygene controlling viability [21], the load of various nonspecific mutations and/or epigenomic rearrangements in DNA made genome unstable [3, 13], mutations of genes controlling fidelity of main processes in DNA (replication, reparation,

transcription and so on) [22], mutations in hyper variable loci [16, 17]. The common trait of all mechanisms suggested is their multiple target origin. Presumable sequence of steps leading to the radiation genetic effects described could be the following: the load of various initial radiation lesions in DNA of parental germ cells initiates the generalized response of progeny genome, manifesting as chromosomal instability, followed by enhanced mutation rate. So the probability of mutations in genes involved in cell transformation, increases as well as in genes responsible for maintain of normal cell functions. As a consequence - increased cancer risk and impaired fitness in the progeny of irradiated parents.
The expression of radiation genetic effects manifested as increased cancer risk and non-carcinogenic negative health effects in the progeny of exposed parents is much obvious in animals as compared to humans. It is hardly due to strong prenatal selection of affected organisms in humans, because these effects manifest postnatally.
It seems more likely that the detection of such effects is difficult in humans since their expression strongly depends on promotive (life style) factors, which are impossible to control in the offspring of irradiated people. It seems worth to emphasize in this connection the importance of application of various diagnostic tests to detect the predisposition of the progeny of irradiated parents to health effects described. The measure of genomic stability seems to be the effective method for assessment of possible cancer risk.
It was emphasized (3, 13, 15) that the existence of such transmissible radiation genetic effects as genomic instability and negative health effects may have implication for the assessment of genetic risk of ionizing radiation in humans. This estimation should take into account the possible decrease of biological quality of

descendants of irradiated parents, causing the predisposition to diseases and the unforeseen elevation of mutational rate.
The finding of new radiation genetic consequences of radiation (carcinogenic and non-carcinogenic negative health effects) gave us the reason to propose the similarity between the somatic and genetic effects of ionizing radiation [3].
Actually somatic consequences of ionizing radiation includes early (acute radiation disease) and late (carcinogenesis, nonspecific radiation pathology) effects.
The early one is due to cell death, leading to exhaustion of proliferative tissues.
Radiation induced carcinogenesis is accompanied by proliferation of cell clones and appearance of additional ("plus") tissue. Non-carcinogenic radiation pathology
(accelerated aging) seems to be the result of functional failure, increased mortality rate of parenchyma cells and substitution of them for nondifferentiated tissue elements
The recent knowleges on the genetic consequences of radiation also permit to divide them into early (acute) and late ones. Early effects comprise the severe disorders in the progeny of irradiated parents described above. Like early somatic effects they seem to be associated with the tissue distraction due to cell death. Both effects are likely to be due to -gross chromosomal, genomic and gene mutations with harmful dominant effects.
It became obvious that increased cancer risk previously known as somatic radiation effect, characterizes as well the progeny of irradiated parents. [6, 8] The genomic instability demonstrated in the mitotic progeny of irradiated cells [23], has been discovered as well in the progeny of irradiated parents. [3, 6] The genetic background of these somatic and genetic effects is likely to be of multitarget origin

and include the load of various DNA injuries causing the increased rate of mutations including those involved in carcinogenesis.
Late radiation pathology (accelerated aging) comprising different negative health effects in irradiated individuals [24] is quite similar to the genetic effect manifested as decreased fitness of the progeny of irradiated parents. The casual events underlain these effects are .presumably the same which was proposed for the increased cancer risk – the load of DNA lesions which induces functional inferiority of cell genome. Thus the phenomenology resemblance of somatic and genetic effects of ionizing radiation provides supportive evidence on the similarity in pathogenic mechanisms of their origin.
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