Non cancer effects (and in particular cardio-vascular effects) related to low doses of radiation (PhD)

Whilst most of the evidence for late health effects following radiation exposure relates to the induction of cancer, there has been increasing interest in recent years in the development of non-cancer diseases.   At present, the strongest evidence for raised risks of mortality from non-cancer diseases following radiation exposure comes from the Japanese atomic bomb survivors and from studies of cancer patients given radiotherapy. These studies indicate increased risks following high dose exposure, particularly for cardiovascular disease, immunological change and the development of lens opacity as well as for cognitive effects (for this later, only when irradiation occurred in utero during the period of brain development). However, it is unclear at present whether risks persist down to low doses. 

Epidemiological evidence linking these end-points to low dose exposures is strongest for cardiovascular effects and will be the focus of this PhD thesis. The acute damaging effects of high dose exposures of ionizing radiation on the endothelial cell system is known (endothelial cells represent the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall). Indeed, when these particular cells are irradiated, loss of cell-cell integrity, failure of fluid barrier maintenance, cell death without replacement and new phenotype are observed and recognised. However, at low doses there is no evidence for the development of acute and/or chronic radiation pathology.

Epidemiological studies of cardiovascular morbidity seem to indicate that damage to the vasculature may indeed be a late effect of low dose of irradiations. Furthermore, the pathogenesis of radiation-induced heart disease has not been studied in detail. Pathohistologic studies suggest that microvascular damage plays a crucial role in the development of radiation-induced cardiovascular disease. In addition, radiation may increase atherosclerotic lesions in the coronary arteries. Another aspect to note is that the full interpretation of this epidemiological data for the purposes of radiation protection at low doses and specially linked to cardiovascular diseases is hindered by the almost complete lack of knowledge about the biological and molecular mechanisms of the radiation effects.

Within this PhD, it is therefore intended to study in vitro at the morphological, biochemical as well as the molecular levels the effects of low doses of radiation on endothelial cells using a series of established endothelial cell lines and primary endothelial cell cultures. A major goal will be the investigation of early molecular, proinflammatory and prothrombotic changes as well as cell integrity and immunologic influences following low doses of irradiation. Changes in pro-inflammation and thrombosis responses through the precise analyses of secreted cytokines and their respective gene expression will be performed at different times after irradiation. Immunochemical analyses in order to visualise the effects of radiation on the cytoskeleton will also be investigated.

Gene expression of the whole genome will be performed in those endothelial cells after irradiation. Genes showing radiation-specific gene changes will be further studied. These key genes will be validated by a second technology (quantitative PCR) developed on extracts from in vivo irradiated cardiovascular samples and the time course and dose response of changes in the radiation response markers of the endothelial cell genome will be followed in vivo in animal models of heart irradiation.