title: The similar neurotoxic effects of nanoparticulate and ionic silver in vivo and in vitro.
abstract: We compared the neurotoxic effects of 14 nm silver nanoparticles (AgNPs) and ionic silver, in the form of silver acetate (AgAc), in vivo and in vitro. In female rats, we found that AgNPs (4.5 and 9 mg AgNP/kg bw/day) and ionic silver (9 mg Ag/kg bw/day) increased the dopamine concentration in the brain following 28 days of oral administration. The concentration of 5-hydroxytryptamine (5-HT) in the brain was increased only by AgNP at a dose of 9 mg Ag/kg bw/day. Only AgAc (9 mg Ag/kg bw/day) was found to increase noradrenaline concentration in the brain. In contrast to the results obtained from a 28-day exposure, the dopamine concentration in the brain was decreased by AgNPs (2.25 and 4.5mg/kg bw/day) following a 14-day exposure. These data suggest that there are differential effects of silver on dopamine depending on the length of exposure. In vitro, AgNPs, AgAc and a 12 kDa filtered sub-nano AgNP fraction were used to investigate cell death mechanisms in neuronal-like PC12 cells. AgNPs and the 12 kDa filtered fraction decreased cell viability to a similar extent, whereas AgAc was relatively more potent. AgNPs did not induce necrosis. However, apoptosis was found to be equally increased in cells exposed to AgNPs and the 12kDa filtered fraction, with AgAc showing a greater potency. Both the mitochondrial and the death receptor pathways were found to be involved in AgNP- and AgAc-induced apoptosis. In conclusion, 14 nm AgNPs and AgAc affected brain neurotransmitter concentrations. AgNP affected 5-HT, AgAc affected noradrenaline, whereas both silver formulations affected dopamine. Furthermore, apoptosis was observed in neuronal-like cells exposed to AgNPs, a 12 kDa filtered fraction of AgNP, and AgAc. These findings suggest that ionic silver and a 14 nm AgNP preparation have similar neurotoxic effects; a possible explanation for this could be the release and action of ionic silver from the surface of AgNPs.
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark. nilha@food.dtu.dk
authors.forename: Niels
authors.initials: N
authors.lastname: Hadrup
authors.forename: Katrin
authors.initials: K
authors.lastname: Loeschner
authors.forename: Alicja
authors.initials: A
authors.lastname: Mortensen
authors.forename: Anoop K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Klaus
authors.initials: K
authors.lastname: Qvortrup
authors.forename: Erik H
authors.initials: EH
authors.lastname: Larsen
authors.forename: Henrik R
authors.initials: HR
authors.lastname: Lam
mesh_terms: D000085:Acetates / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D053768:Metal Nanoparticles; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D016716:PC12 Cells; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D053218:Receptors, Death Domain / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D018030:Silver Compounds / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000085:Acetates; D053218:Receptors, Death Domain; D018030:Silver Compounds; C103100:silver acetate; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine