title: Metabolic fate of ultratrace levels of GeCl(4) in the rat and in vitro studies on its basal cytotoxicity and carcinogenic potential in Balb/3T3 and HaCaT cell linesdagger.
abstract: The use of germanium (Ge) and the possibility of exposure to trace and ultratrace amounts of this element is increasing. Germanium is widely used in the industrial field as a semiconductor and also as a dietary supplement, an elixir to 'promote health and cure disease' (e.g. cancer and AIDS). More recently, germanium nanoparticles, ranging in size from 60 to 80 nm, have been developed as a potential spleen imaging agent. Like other metal-based nanoparticles used in nanomedicine, Ge nanoparticles may release trace and ultratrace amounts of Ge ions when injected. The metabolic fate and toxicity of these ions still needs to be evaluated. In this study the metabolic fate of a cationic tetravalent Ge species was studied in vivo by injecting rats i.p. with ultratrace amounts of Ge (80 ng kg(-1)) as [(68)Ge]GeCl(4). The cytotoxicity and carcinogenic potential was assessed in vitro using immortalised human skin keratinocytes and mouse fibroblasts (HaCaT and Balb/c 3T3 cell lines, respectively). At 24 h post-exposure Ge was poorly retained in rat tissues (kidney, liver, intestine, femur, spleen and the heart were the organs with the highest Ge concentration). In the blood, Ge was rapidly cleared, being almost equally distributed between plasma and red blood cells. The excretion was mainly via the urine. The hepatic and renal intracellular distribution showed the highest recovery of Ge in the cytosol and the nuclear fractions. Chromatographic separation and ultrafiltration experiments on kidney and liver cytosols showed that the bulk of Ge was associated with low molecular weight components, representing a 'mobile pool' of the element in the body. However, a significant part of the element was able to interact with biological macromolecules which could be responsible for the presence of Ge in the liver and kidney after 7 days. The in vitro experiments confirmed the low degree of cytotoxicity of GeCl(4) both in HaCaT and Balb/3T3. The latter model was more sensitive to the toxic effects induced by Ge as shown by a colony forming efficiency (CFE) greater than 70% at 700 microm of exposure. At the highest exposure concentration tested (700 microm) GeCl(4) failed to induce morphological neoplastic transformation of the cells, suggesting for the first time that a cationic form of Ge ions has no carcinogenic potential. This supports the results of the only study reported in mice, treated orally long-term to an anionic species of Ge such as sodium germanate (Kanisawa and Schroeder, 1967).
authors.affiliation: CeSI, Ageing Research Center, G. d'Annunzio University Foundation, 66100 Chieti, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Sabbioni
authors.forename: S
authors.initials: S
authors.lastname: Fortaner
authors.forename: S
authors.initials: S
authors.lastname: Bosisio
authors.forename: M
authors.initials: M
authors.lastname: Farina
authors.forename: R
authors.initials: R
authors.lastname: Del Torchio
authors.forename: J
authors.initials: J
authors.lastname: Edel
authors.forename: M
authors.initials: M
authors.lastname: Fischbach
mesh_terms: D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects*; D005857:Germanium / Q000378:metabolism* / Q000633:toxicity*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000166:cytology / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: D002273:Carcinogens; D005857:Germanium