TURBO

Uranium chemical toxicity is a subject of concern for the general population as various anthropic activities have led to a substantial increase of the uranium background concentration in the environment. If the actual trend is to reduce nuclear energy in Western Europe, other countries like Russia, China or India have been substantially investing in the development of new nuclear power-plants. Thus the use of uranium will certainly remain a concern for the future generations, worldwide. Most experimental studies related to the health effects of uranium were dedicated to its radiotoxicity and its acute chemical toxicity (nephrotoxicity). Some animal studies and few epidemiological studies also considered chronical exposure, but the data are still too sparse to derive a toxicological threshold associated with long-term effects. Moreover, although the skeleton is well known to be the main site of uranium long-term accumulation, the chemical effects of uranium on bone health remain an open question. Bone is a complex organ composed of an organo-mineral matrix, undergoing constant remodeling thanks to a tightly regulated cellular system. Therefore the question of how uranium interacts with the physiological environment and accumulates in bone matrix can only be answered using a multi-level and multidisciplinary approach, which relies on both molecular and cellular understanding. Recently, we (the consortium of this project) demonstrated that uranium is transported in the blood as complexes with proteins involved in bone metabolism. In addition, we showed that this actinide element affects the main functions of bone cells in vitro, i.e. construction and resorption. The present project represents the first comprehensive mechanistic investigation of uranium interaction with the bone matrix. We propose to study the exchange mechanisms between uranium and bone in vitro and ex vivo, at three different levels: the molecular level, with synthetic biomimetic bone matrices and peptides modeling relevant biological binding sites in proteins; the biochemical level, with bone matrix proteins and circulating proteins; and the cellular level, involving osteoblast/osteocyte and osteoclast functions. This innovative global approach using a multi-level strategy will lead to a better understanding of the mechanisms involved in bio-mineralization of uranium and will help to design and assess new detoxification (also called decorporation) agents for this metal. Moreover, the interdisciplinary procedures developed in this study are of general interest and will bring added value regarding other toxic metals which also accumulate in bone. ______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________