Transformation of human osteoblast cells to the tumorigenic phenotype by depleted uranium-uranyl chloride.

Abstract

Depleted uranium (DU) is a dense heavy metal used primarily in military applications. Although the health effects of occupational uranium exposure are well known, limited data exist regarding the long-term health effects of internalized DU in humans. We established an in vitro cellular model to study DU exposure. Microdosimetric assessment, determined using a Monte Carlo computer simulation based on measured intracellular and extracellular uranium levels, showed that few (0.0014%) cell nuclei were hit by alpha particles. We report the ability of DU-uranyl chloride to transform immortalized human osteoblastic cells (HOS) to the tumorigenic phenotype. DU-uranyl chloride-transformants are characterized by anchorage-independent growth, tumor formation in nude mice, expression of high levels of the k-ras oncogene, reduced production of the Rb tumor-suppressor protein, and elevated levels of sister chromatid exchanges per cell. DU-uranyl chloride treatment resulted in a 9.6 (+/- 2.8)-fold increase in transformation frequency compared to untreated cells. In comparison, nickel sulfate resulted in a 7.1 (+/- 2.1)-fold increase in transformation frequency. This is the first report showing that a DU compound caused human cell transformation to the neoplastic phenotype. Although additional studies are needed to determine if protracted DU exposure produces tumors in vivo, the implication from these in vitro results is that the risk of cancer induction from internalized DU exposure may be comparable to other biologically reactive and carcinogenic heavy-metal compounds (e.g., nickel).ImagesFigure 1Figure 2Figure 3

Depleted and Natural Uranium: Chemistry and Toxicological Effects

“…Since uranyl nitrate has a high affinity for phosphate, Lin et al (1993) speculated that the cytotoxic and genotoxic effects might have resulted from the uranyl nitrate binding to phosphate groups on DNA. In a similar study, Miller et al (1998b) determined that depleted uranium-uranyl chloride (10 µM) could transform immortalized human osteosarcoma (HOS) cells to the tumorigenic phenoype. While there was no effect on cell survival or cell growth, there was a twofold increase in SCE induction.…”

Evaluation of the Health Risks of Embedded Depleted Uranium (DU) Shrapnel on Pregnancy and Offspring Development

“…Were AFRRI interested in pursuing this line of research, a study into possible effects on mutagenicity or oncogene expression in the rats exposed in utero to DU, as has been seen in tissues from animals with direct exposure to DU 32,33 . The rat offspring are exposed to some amount of uranium, as evidenced by the graphs showing fetal levels of uranium, throughout development.…”

Particulate Depleted Uranium Is Cytotoxic and Clastogenic to Human Lung Cells

“…DU particles inhaled by rats showed increased DNA damage and inflammatory effects (13). Studies in human osteosarcoma cells indicate that DU can induce transformation (14) and cause cytotoxicity, genomic instability, and micronuclei formation (7). Soluble DU caused micronuclei formation, sister chromatid exchanges, DNA adducts, hprt mutations, and chromosomal aberrations in Chinese hamster ovary (CHO) cells (15,16).…”