title: Increased 8-hydroxydeoxyguanosine in kidney and liver of rats continuously exposed to copper.
abstract: Copper is a ubiquitous metal in the environment, it is a component of dental casting gold alloys and dental amalgams, and it is a main component in some intrauterine contraceptive devices (IUDs). Since copper materials implanted in the human body corrode and release ions into the surrounding tissue, the potential toxicity caused by contact of this metal with bodily fluids needs to be evaluated. We implanted male Wistar rats with osmotic mini pumps that continuously administered saline, CuCl2, or a copper chelate, cupric nitrilotriacetate (Cu-NTA), at a rate of 4 mg copper/kg body wt/day. This experimental design maintained serum copper concentrations at a level 30-70% (CuCl2) or 100-120% (Cu-NTA) higher than in untreated controls. At different times postimplantation, we measured the levels of 8-hydroxydeoxyguanosine (8-OHdG) in DNA of kidney, liver, and tissue surrounding the pump implant, since production of 8-OHdG has been associated with mutagenesis and carcinogenesis. Hepatic and renal levels of 8-OHdG in CuCl2- or Cu-NTA-treated animals were significantly higher than in control animals. In contrast, histopathologic changes in kidneys and livers of rats exposed to CuCl2 and Cu-NTA were limited to mild changes involving hepatic focal necrosis and slightly increased mitotic activity in the renal proximal tubules. These observations suggest that levels of 8-OHdG could be an early marker of copper toxicity. It is unlikely that the high levels of copper at which we observed DNA modification will be encountered after occupational or environmental exposure. A different situation could be found around medical devices that include copper, particularly IUDs, where the amount of copper administered in our experiments could be released in the uterus of women after a few months of continued IUD use.
authors.affiliation: Molecular Biology Branch, Food and Drug Administration, Rockville, Maryland 20857.
authors.forename: S
authors.initials: S
authors.lastname: Toyokuni
authors.forename: J L
authors.initials: JL
authors.lastname: Sagripanti
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001672:Biocompatible Materials / Q000633:toxicity*; D003300:Copper / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D009942:Organometallic Compounds / Q000633:toxicity; D019736:Prostheses and Implants / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001672:Biocompatible Materials; D009942:Organometallic Compounds; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C060581:cupric nitrilotriacetate; D003849:Deoxyguanosine; D009571:Nitrilotriacetic Acid