title: TLR4 signaling is involved in brain vascular toxicity of PCB153 bound to nanoparticles.
abstract: PCBs bind to environmental particles; however, potential toxicity exhibited by such complexes is not well understood. The aim of the present study is to study the hypothesis that assembling onto nanoparticles can influence the PCB153-induced brain endothelial toxicity via interaction with the toll-like receptor 4 (TLR4). To address this hypothesis, TLR4-deficient and wild type control mice (males, 10 week old) were exposed to PCB153 (5 ng/g body weight) bound to chemically inert silica nanoparticles (PCB153-NPs), PCB153 alone, silica nanoparticles (NPs; diameter, 20 nm), or vehicle. Selected animals were also subjected to 40 min ischemia, followed by a 24 h reperfusion. As compared to exposure to PCB153 alone, treatment with PCB153-NP potentiated the brain infarct volume in control mice. Importantly, this effect was attenuated in TLR4-deficient mice. Similarly, PCB153-NP-induced proinflammatory responses and disruption of tight junction integrity were less pronounced in TLR4-deficient mice as compared to control animals. Additional in vitro experiments revealed that TLR4 mediates toxicity of PCB153-NP via recruitment of tumor necrosis factor-associated factor 6 (TRAF6). The results of current study indicate that binding to seemingly inert nanoparticles increase cerebrovascular toxicity of PCBs and suggest that targeting the TLR4/TRAF6 signaling may protect against these effects.
authors.affiliation: Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.forename: Jeong June
authors.initials: JJ
authors.lastname: Choi
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Eum
authors.forename: Sylvia
authors.initials: S
authors.lastname: Daunert
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D002544:Cerebral Infarction / Q000473:pathology; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D004785:Environmental Pollutants; D048029:TNF Receptor-Associated Factor 6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D011078:Polychlorinated Biphenyls; C014024:2,4,5,2',4',5'-hexachlorobiphenyl