i) to provide an experimental model and a basis by which to estimate the risk of cancer occurrence in children born to fathers exposed to carcinogens;
ii) to investigate the possible contribution of prenatal events to the origin of cancer;
iii) to investigate whether the prezygotic exposure of male mice sperm cells to ionizing radiation or a chemical carcinogen would result in an increased risk in the untreated progeny, and/or an increased susceptibility to cancer following exposure to a promoting agent during adult life;
iv) to clarify the mechanisms by which the effects of carcinoges are transmitted in germ cells;
v) to clarify the various steps and the molecular characteristics of postnatal carcinogenesis in the progeny of males exposed prior to conception.
It has been subject for controversial discussion for many years whether preconceptional parental exposure to some environmental or industrial chemicals as well as to ionizing radiation leads to an increased tumour incidence in progeny of the exposed persons. The proposed study will provide indications (in the F1 descendants of the CBA/J mouse strain) of the extent to which the tumour rate and spectrum may be influenced, by exposure of the male parent to X-radiation or a chemical carcinogen/mutagen prior to conception. The mating of males with untreated females at three time points after exposure to X-rays or urethane (ethyl carbamate) will imply the fertilization by sperm cells exposed to carcinogenic mutagenic agents at three different stages of spermatogenesis. The carcinogens (X-rays and urethane) chosen for the treatment of the male mice are effective in multigeneration carcinogenesis studies. As lung tumours are rather common in several mouse strains and can be induced by many agents, the mouse lung will be one of the preferential targets of the genetic transmission of a cancer risk. Other potential target organs are the liver and skin. Urethane is one of the most widely studied carcinogens/promoters used in such models. It is known to substantially increase the incidence and to accelerate the time of appearance of lung tumours even after one single application.
In the project it is proposed to divide F1 descendants from males exposed prior to mating with untreated females into two groups: one left untreated to observe the consequence of prezygotic exposure per se, and the other to be exposed to a tumour promoter (urethane). The latter group will allow the clarification of whether the prezygotic exposure of the male parent has or has not modified the response of the F1 group to the exposure to another carcinogen as well as to a tumour promoter. This is of particular relevance, since humans are certainly exposed during their lifetime to a variety of promoters to the point that, in most instances, the exposure to promoters may represent the rate limiting factors for human tumours. Thus, the study design fulfils the concept of multistage and multifactorial carcinogenesis, in which the prezygotic exposure to a carcinogen acts as an initiating event and the postnatal exposure to promoting agents may be the stimulus to manifest the carcinogenic effects. Apart from the routine histopathological examinations, molecular biological analyses of the ras oncogene mutations will be performed, using DNA from the lung, liver and skin tumours, as well as from normal tissues. These analyses will be useful not only in examining a possible mutation of germ cell oncogenes, but also in differentiating "induced" tumours from "spontaneous" tumours. Additional to the analyses of oncogene mutations, inactivation mechanisms (mutations and deletions) of tumour suppressor genes, i.e. of the retinoblastoma (Rb)-gene or the p53-gene, will be investigated, because alterations of the p53 gene occur as somatic mutations in human cancers, and also as germline mutations in some cancer-prone families.
Funding SchemeCSC - Cost-sharing contracts