Radiation- and Depleted Uranium-Induced Carcinogenesis Studies: Characterization of the Carcinogenic Process and Development of Medical Countermeasures

摘要

External or internal contamination from radioactive elements during military operations or a terrorist attack is a serious threat to military and civilian populations. External radiation exposure could result from conventional military scenarios including nuclear weapons use and low-dose exposures during radiation accidents or terrorist attacks. Alternatively, internal radiation exposure could result from depleted uranium exposure via DU shrapnel wounds or inhalation. The long-term health effects of these types of radiation exposures are not well known. Furthermore, development of pharmacological countermeasures to low-dose external and internal radiological contamination is essential to the health and safety of both military and civilian populations. The purpose of these studies is to evaluate low-dose radiation or DU-induced carcinogenesis using in vitro and in vivo models, and to test safe and efficacious medical countermeasures. A third goal of these studies is to identify biomarkers of both exposure and disease development. Initially, we used a human cell model (human osteoblast cells, HOS) to evaluate the carcinogenic potential of DU in vitro by assessing morphological transformation, genotoxicity (chromosomal aberrations), mutagenic (HPRT loci), and genomic instability. As a comparison, low-dose cobalt radiation, broad-beam alpha particles, and other military-projectile metals, i.e., tungsten mixtures, are being examined. Published data from our laboratory demonstrated that DU exposure in vitro to immortalized HOS cells is neoplastically transforming, mutagenic, genotoxic, and induces genomic instability. In vitro data demonstrate that radiation-specific damage is involved in the DU carcinogenic process in vitro. Furthermore, evaluation of the mutational spectrum of DU- induced HPRT mutations suggests a differential response between DU- and 60Co- irradiated cells.