title: Effects of PAMAM dendrimers in the mouse brain after a single intranasal instillation.
abstract: Dendrimers are highly branched spherical nanomaterials produced for use in diagnostic and therapeutic applications such as a drug delivery system. The toxicological profiles of dendrimers are largely unknown. We investigated the in vivo effects of nasal exposure to polyamidoamine (PAMAM) dendrimers on their effects on neurological biomarkers in the mouse brain. A single dose of PAMAM dendrimers (3 or 15μg/mouse) was intranasally administered to 8-week old male BALB/c mice. Twenty-four hours after administration, the olfactory bulb, hippocampus, and cerebral cortex were collected and potential biomarkers in the blood and brain were examined using blood marker, microarray and real-time RT-PCR analyses. No remarkable changes in standard serum biochemical markers were observed in the blood. A microarray analysis showed the alterations of the genes expression level related to pluripotent network, serotonin-anxiety pathway, TGF-beta receptor signaling, prostaglandin synthesis-regulation, complement-coagulation cascades, and chemokine-signaling pathway and non-odorant GPCR signaling pathways in brain tissues. Brain derived-neurotrophic factor mRNA was up-regulated in the hippocampus and cerebral cortex in mice treated with a high dose of dendrimers. These findings suggest that PAMAM dendrimers may reach the brain via the systemic circulation or an olfactory nerve route after intranasal instillation, and indicate that a single intranasal administration of PAMAM dendrimers may potentially lead to neuronal effects by modulating the gene expression of brain-derived neurotrophic factor signaling pathway.
authors.affiliation: Center for Environmental Health Sciences, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Tin-Tin
authors.initials: TT
authors.lastname: Win-Shwe
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan. Electronic address: hsone@nies.go.jp.
authors.forename: Hideko
authors.initials: H
authors.lastname: Sone
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Yoshika
authors.initials: Y
authors.lastname: Kurokawa
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Center for Environmental Health Sciences, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nitta
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Seishiro
authors.initials: S
authors.lastname: Hirano
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050091:Dendrimers / Q000008:administration & dosage / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000097:blood / Q000209:etiology* / Q000235:genetics; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D015415:Biomarkers; D050091:Dendrimers; D005819:Genetic Markers; D018836:Inflammation Mediators; D009414:Nerve Growth Factors; C104700:PAMAM Starburst
keywords: Biomarkers; Mouse; Nanomaterials; Neurotoxicity; PAMAM dendrimers