Tumors of the nervous system most often occur in both children and adults as sporadic events with no family history of the disease, but they are also among the clinical manifestations of a significant number of familial cancer syndromes, including familial retinoblastoma, neurofibromatosis 1 and 2, tuberous sclerosis, and Cowden, Turcot, Li-Fraumeni and nevoid basal cell carcinoma (Gorlin) syndromes. All of these syndromes involve transmissible genetic risk resulting from loss of a functional allele, or inheritance of a structurally defective allele, of a specific gene. These genes include RB1, NF1, NF2, TSC1, TSC2, TP53, PTEN, APC, hMLH1, hPSM2, and PTCH, most of which function as tumor suppressor genes. The same genes are also observed in mutated and inactive forms, or are deleted, in tumor cells in sporadic cases of the same tumors. The nature of the mutational events that give rise to these inactivated alleles suggests a possible role of environmental mutagens in their causation. However, only external ionizing radiation at high doses is clearly established as an environmental cause of brain, nerve and meningeal tumors in humans. Transplacental carcinogenesis studies in rodents and other species emphasize the extraordinary susceptibility of the developing mammalian nervous system to carcinogenesis, but the inverse relationship of latency to dose suggests that low transplacental exposures to genotoxicants are more likely to result in brain tumors late in life, rather than in childhood. While not all neurogenic tumor-related genes in humans have similar effects in experimental rodents, genetically engineered mice (GEM) increasingly provide useful insights into the combined effects of multiple tumor suppressor genes and of gene-environment interactions in the genesis of brain tumors, especially pediatric brain tumors such as medulloblastoma.

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High frequencies of inherited DNA sequence variations (polymorphisms) are found in the human population. The involvement of polymorphic genes (especially for chemical metabolism and DNA repair) in the development of cancer is under intensive investigation. In our studies, we have irradiated blood lymphocytes from normal non-smokers with γ-rays or UV-light to investigate genotypes and DNA repair functions. We found that XRCC1 399Gln and XRCC3 241Met were deficient in the repair of γ-ray-but not UV-light-induced DNA damage that led to the expression of chromosome aberrations; therefore the variant genotypes are defective in base excision repair. The reverse was found with XPD 312Asn and XPD 751Gln; therefore they are defective in nucleotide excision repair. XRCC1 194Trp, OGG1 326Cys and APE1 148Glu had no DNA repair deficiency based on our experimental conditions. In another study, we investigated the role of some of these genes on the development of lung cancer. We found a significant increase of chromosome aberrations in patients and controls that had the XPD 751Gln and GSTM1 null genotypes, indicating a mechanistic causation of the disease. Therefore, inheritance of susceptibility genes can have significant impact on disease burden in the population. On the other hand, there are many questions that need to be addressed in order to evaluate the impact of susceptibility on cancer. These questions include the understanding of combinations of different polymorphic genes for susceptibility and of specific disease susceptibility for different ethnic populations.

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The congenital malformation gastroschisis has a genetic disposition in the inbred mouse strain HLG/Zte. It is increased after preconceptional irradiation of males or females. Radiation exposures during the meiotic stages are most efficient. This malformation can also be induced by ionising radiation when the exposure takes place during the preimplantation period especially during the zygote stage. This latter effect can be transmitted to the next mouse generation. Other macroscopically visible or skeletal malformations are not significantly induced under these experimental conditions. These latter malformations are increased by radiation exposures during major organogenesis. The mechanisms for the development of the effects are different. Radiation exposure of the mouse zygote (1 to 3 hours p.c.) also leads to the induction of genomic instability in skin fibroblasts of the fetus. This phenomenon also occurs in a mouse strain (C57BL/6J) which is not susceptible to radiation-induced gastroschisis during the preimplantation period. The genomic instability is transmitted to the next mouse generation. During genomic instability chromatide breaks are dominating as in non-exposed cells. With respect to "spontaneous" malformations gastroschisis is dominating in HLG/Zte mice. Late radiation effects seem to have similar patterns as observed in non-exposed subjects, however, the rates are increased after irradiation.

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Many studies have confirmed that radiation can induce genomic instability in whole body systems. Although the molecular mechanisms underlying induced genomic instability are not known at present, this interesting phenomenon could be the manifestation of a cellular fail-safe system in which fidelity of repair and replication is down-regulated to tolerate DNA damage. Two features of genomic instability namely, delayed mutation and untargeted mutation, require two mechanisms of `damage memory' and `damage sensing, signal transduction and execution' to induce mutations at a non damaged-site. In this report, the phenomenon of transgenerational genomic instability and possible mechanisms are discussed using mouse data collected in our laboratory as the main bases.

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We examined the use of the mouse Pc-3 ESTR (expanded simple tandem repeat) locus and 72 human microsatellite loci as potentially sensitive biomarkers for mutagenic exposures to germ cells in mice and humans respectively. In the mouse work, we treated male mice with TCDD (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin; a chemical known to induce congenital anomalies in humans and mice) and, analysed the F₁ fetuses for Pc-3 mutations. Although the incidence of anomalies was higher in the TCDD group, there were no induced mutations. However, respiratory distress syndrome (RDS) was observed in 3 of 7 fetuses born to male mice which were treated with TCDD and which showed abnormal length of Pc-3 allele. In the human studies, the children of Chernobyl liquidators were examined for mutations at a total of 72 (31 autosomal, 1 X-linked and 40 Y-linked) microsatellite loci. This study was prompted by earlier findings of increases in microsatellite mutations in barn swallows and wheat in the highly contaminated areas after the Chernobyl accident. We examined 64 liquidator families (70 children) and 66 control families (70 children). However, no increases in mutation rates were found. The estimated mean dose to the liquidators was about 39 mSv and this might be one possible reason why no increases of mutations could be found.

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Delayed appearance of induced mutations has been observed in Drosophila, plants, rodents and recently in humans. The significance of this phenomenon is now recognized especially after the pioneering work of Nomura demonstrating transgenerational tumour induction in mice following treatment with urethane or ionizing radiation. A brief review of the literature on transgenerational genetic effects, namely, chromosomal aberrations and mutations, in rodents and humans is presented here.

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The origin and transmission of de novo chromosome mutations were reviewed on the basis of our chromosome studies in retinoblastoma patients and male infertility. In a series of 264 sporadic retinoblastoma families, gross chromosome rearrangements involving the RB1 locus were identified in 23 cases (8.7%), of which 16 were non-mosaic and 7 were mosaic mutations. The newly formed chromosome mutations, whether they were non-mosaic or mosaic, had a strong bias towards paternally derived chromosome, indicating that they shared a common mechanism where a pre-mutational event or instability is carried over to zygote by sperm and manifested as gross chromosome mutation at the early stages of development. The de novo chromosome mutations are preferentially transmitted through female carriers. This transmission bias is consistent with the finding of higher frequencies of translocation carriers in infertile men (7.69% versus 0.27% in general populations) in whom meiotic progression is severely suppressed, possibly through activation of meiotic checkpoints. Such a meiotic surveillance mechanism may minimize the spreading of newly-arisen chromosome mutations in populations. A quantitative model of meiotic surveillance mechanism is proposed and successfully applied to the published data on `humped' dose-response curves for radiation-induced spermatogonial reciprocal translocations in several mammalian species.

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The 2001 report of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) on `Hereditary effects of radiation' incorporates two important concepts that have emerged from advances in radiation genetics and molecular biology: (a) most radiation-induced mutations are DNA deletions, often encompassing multiple genes; however, because of structural and functional constraints, only a proportion of induced deletions may be compatible with viability and hence recoverable in the progeny and (b) viability-compatible DNA deletions induced in human germ cells are more likely to cause multi-system developmental abnormalities rather than single-gene diseases. The work reported in this paper pursues these concepts further: it examines how mechanistic insights gained from studies of repair of radiation-induced DNA double-strand breaks (DSBs) in mammalian somatic cells and from those on the origin of deletions in human genomic disorders can be extended to germ cells the aim being the development of a framework to predict regions of the human genome that may be susceptible to radiation-induced deletions. A critical analysis of the available information permits the hypothesis that in stem cell spermatogonia, most induced deletions may arise via the non-homologous end joining (NHEJ) mechanism of DSB repair whereas in irradiated oocytes, the main mechanism is likely to be non-allelic homologous recombination (NAHR) between misaligned region-specific segmental duplications that are present in the genome (NAHR is an error-prone form of homologous recombination repair). Should this hypothesis turn out to be valid, then it is possible to build on the structural and functional aspects of genomic knowledge to devise strategies to predict where in the genome deletions may be induced by radiation, their extent and their potential phenotypes.

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Genetic studies in the offspring of atomic bomb survivors have been conducted since 1948 at the Atomic Bomb Casualty Commission and its successor, the Radiation Effects Research Foundation, in Hiroshima and Nagasaki. Past studies include analysis of birth defects (untoward pregnancy outcome; namely, malformation, stillbirth, and perinatal death), chromosome aberrations, alterations of plasma and erythrocyte proteins as well as epidemiologic study on mortality (any cause) and cancer incidence (the latter study is still ongoing). There is, thus far, no indication of genetic effects in the offspring of survivors. Recently, the development of molecular biological techniques and human genome sequence databases made it possible to analyze DNA from parents and their offspring (trio-analysis). In addition, a clinical program is underway to establish the frequency of adult-onset multi-factorial diseases (diabetes mellitus, high blood pressure, and cardiovascular disease etc) in the offspring. The complementary kinds of data that will emerge from this three-pronged approach (clinical, epidemiologic, and molecular aspects) promise to shed light on health effects in the offspring of radiation-exposed people.

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Base substitution mutations are far more common in human males than in females, and the frequency increases with paternal age. Both can be accounted for by the greater number of pre-meiotic cell divisions in males, especially old ones. In contrast, small deletions do not show any important age effect and occur with approximately equal frequency in the two sexes. Mutations in most genes include both types, and the sex and paternal age effect depends on the proportion of the two types. A few traits, of which Apert Syndrome is best understood, are mutation hot spots with all the mutations occurring in one or two codons, usually at one nucleotide. They occur with very high frequency almost exclusively in males and the frequency increases rapidly with paternal age. It has been suggested that the mutant cells have a selective advantage in the male germ-line prior to meiosis. Evidence for this surprising, but important, hypothesis is discussed. A possible mechanism is the conversion of asymmetrical stem-cell divisions into symmetric ones. Some traits with complex etiology show a slight paternal age effect. There is also a short discussion of the high deleterious mutation rate and the role of sexual reproduction in reducing the consequent mutation load.

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Parental exposure of mice to radiation and chemicals causes a variety of adverse effects (e.g., tumors, congenital malformations and embryonic deaths) in the progeny and the tumor-susceptibility phenotype is transmissible beyond the first post-radiation generation. The induced rates of tumors were 100-fold higher than those known for mouse specific locus mutations. There were clear strain differences in the types of naturally-occurring and induced tumors and most of the latter were malignant. Another important finding was that germ-line exposure elicited very weak tumorigenic responses, but caused persistent hypersensitivity in the offspring for the subsequent development of cancer by the postnatal environment.
Activations of oncogenes, ras, mos, abl, etc. and mutations in tumor suppressor genes such as p53 were also detected in specific tumors in cancer-prone descendants. However, the majority of tumors observed in the progeny were those commonly observed in the strains that were used and oncogene activations were rarely observed in these tumors. It can be hypothesized that genetic instability modifies tumor occurrence in a transgenerational manner, but so far no links could be established between chromosomal and molecular changes and transmissible tumor risks. Our data are consistent with the hypothesis that cumulative changes in many normal but cancer-related genes affecting immunological, biochemical and physiological functions may slightly elevate the incidence of tumors or fasten the tumor development. This hypothesis is supported by our GeneChip analyses which showed suppression and/or over-expression of many such genes in the offspring of mice exposed to radiation.
In humans, a higher risk of leukemia and birth defects has been reported in the children of fathers who had been exposed to radionuclides in the nuclear reprocessing plants and to diagnostic radiation. These findings have not been supported in the children of atomic bomb survivors in Hiroshima and Nagasaki, who were exposed to higher doses of atomic radiation. However, it will be important to follow the human subjects, especially for adult type cancers and chronic diseases throughout their lives to determine whether the mouse studies can predict human responses.

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