Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of the c-jun-N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mouse brain

Fujimura, Masatake; Usuki, Fusako; Sawada, Masumi; Takashima, Akihiko

doi:10.1016/j.neuro.2009.08.001

Cited by 100 publications

(75 citation statements)

References 34 publications

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Section: Resultsmentioning

confidence: 99%

“…These results suggest that NF-κB is involved, at least in part, in CCL2 expression induced by methylmercury. Transcription factors other than NF-κB are also involved in modulating the expression of chemokines, including CCL2 (Fujimura et al, 2009;Kuper et al, 2012), and these may be involved in chemokine induction by methylmercury.Nuclear transport of NF-κB is inhibited by binding of NF-κB to IκBα in the cytoplasm. IκBα is degraded by oxidative stress and as a result of the activities of TNFα and other cytokines, allowing NF-κB transport into the nucleus to promote transcription of target genes (Hoffmann and Baltimore, 2006;Sumi et al, 2010).…”

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Methylmercury induces CCL2 expression through activation of NF-κB in human 1321N1 astrocytes

et al. 2012

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-Methylmercury is an environmental pollutant that is toxic to the central nervous system; however, the molecular mechanisms underlying its toxicity remain unclear. Methylmercury increases expression of several chemokines in the cerebellum of mice treated with methylmercury. The present study analyzes the mechanism underlying methylmercury-induced chemokine expression using human 1321N1 astrocytes, and shows that methylmercury increases CCL2 expression in these cells. The transcription factor NF-κB is involved in the induction of chemokine expression. Methylmercury increased the level of the NF-κB p65 subunit in the nuclei of 1321N1 cells. The methylmercury-induced increase in CCL2 expression was significantly decreased by suppression of p65 expression by RNA interference. These results suggest that methylmercury induces chemokine expression through activation of NF-κB in human astrocytes.Key words: Methylmercury, Chemokine, CCL2, NF-κB Correspondence: Akira Naganuma (E-mail: naganuma@m.tohoku.ac.jp) LetterThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.37, No.6, 1275-1278 Vol. 37 No. 6 1275 facturer's protocol. Lentivirus was produced in HEK293T cells by co-transfection of the lentiviral vector pGIPZ encoding p65-shRNA and the Trans-Lentiviral Packaging Plasmid Mix (Thermo Fisher Scientific). 1321N1 cells were infected with lentivirus in the presence of polybrene (5 μg/ml) and selected in medium containing puromycin (1 μg/ml). The target sequence of p65 shRNA used was 5'-ACCATCAAGATCAATGGCT-3'. Quantitative real-time PCR (qPCR)Total RNA was isolated from cells using the Isogen II kit (Nippon Gene, Tokyo, Japan) according to the manufacturer's instructions. First-strand cDNA synthesis was carried out using the PrimeScript TM RT reagent kit (Takara, Shiga, Japan). qPCR was performed using SYBR Premix EX Taq (Takara) (Hwang et al., 2011a;Takahashi et al., 2011). PCR primers used were GAPDH, 5'-GGGGAAGCTTGTCAATGG-3' (sense) and 5'-GGCAGTGATGGCATGGACTC-3' (antisense); p65, 5'-CTGCAGTTTGATGATGAAGA-3' (sense) and 5'-TAGGCGAGTTATAGCCTCAG-3' (antisense); and CCL2, 5'-CATTGTGGCCAAGGAGATCTG-3' (sense) and 5'-CTTCGGAGTTTGGGTTTGCTT-3' (antisense). Levels of P65 and CCL2 mRNA were normalized to that of GAPDH. Enzyme-linked immunosorbent assay (ELISA)CCL2 secreted into culture medium was quantified using the Quantikine ELISA kit (R&D Systems, Minneapolis, MN, USA) according to the manufacturer's instructions. Preparation of nuclear and post-nuclear fractions1321N1 cells were lysed in ice-cold hypotonic buffer (10 mM HEPES-KOH [pH 7.9], 1.5 mM MgCl 2 , 10 mM KCl, 1 mM Dithiothreitol [DTT], 0.5 mM phenylmethylsulfonyl fluoride [PMSF]) containing protease inhibitors (Roche Applied Science, Indianapolis, IN, USA) and 10% Nonidet P-40, and centrifuged at 15,000 × g at 4°C. The supernatant (post-nuclear fraction) was removed, and the pellet was resuspended in nuclear lysis buffer (10 mM HEPES-KOH [pH 7.9], 400 mM NaCl, 0.2 mM EDTA, 1.5 mM MgCl 2 , 1 mM DTT, 5% glycerol) containing protease inhibitors (Roche App...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Methylmercury induces CCL2 expression through activation of NF-κB in human 1321N1 astrocytes

et al. 2012

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“…Hematoxylin and eosin staining and NeuN immunohistochemical staining of brain sections Histological analyses were performed as described previously (Fujimura et al 2009). In brief, after 50 days of exposure five brains from five different fish per condition were excised, fixed with 4% paraformaldehyde (Wako Pure Chemical Industries Ltd, Osaka, Japan) in phosphate-buffered saline (SigmaAldrich, St Louis, USA), and embedded in paraffinwax; further, 5-lm coronal sections were cut using a microtome.…”

Section: Mitochondrial Respiration Measurementsmentioning

confidence: 99%

Effects of dietary methylmercury on the zebrafish brain: histological, mitochondrial, and gene transcription analyses

et al. 2011

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The neurotoxic compound methylmercury (MeHg) is a commonly encountered pollutant in the environment, and constitutes a hazard for wildlife and human health through fish consumption. To study the neurotoxic impact of MeHg on piscivorous fish, we contaminated the model fish species Danio rerio for 25 and 50 days with food containing 13.5 μg/g dry weight (dw) of MeHg (0.6 μg MeHg/fish/day), an environmentally relevant dose leading to brain mercury concentrations of 30 ± 4 μg of Hg g(-1) (dw) after 25 days of exposure and 46 ± 7 μg of Hg g(-1) (dw) after 50 days. Brain mitochondrial respiration was not modified by exposure to MeHg, contrary to what happens in skeletal muscles. A 6-fold increase in the expression of the sdh gene encoding the succinate dehydrogenase Fe/S protein subunit was detected in the contaminated brain after 50 days of exposure. An up regulation of 3 genes, atp2b3a, atp2b3b, and slc8a2b, encoding for calcium transporters was noticed after 25 days of exposure but the atp2b3a and atp2b3b were repressed and the slc8a2b gene expression returned to its basal level after 50 days, suggesting a perturbation of calcium homeostasis. After 50 days, we detected the up regulation of glial fibrillary acidic protein and glutathione S-transferase genes (gfap and gst), along with a repression of the glutathione peroxidase gene gpx1. These results match well with a MeHg-induced onset of oxidative stress and inflammation. A transmission electron microscopic observation confirmed an impairment of the optical tectum integrity, with a decrease of the nucleal area in contaminated granular cells compared to control cells, and a lower density of cells in the contaminated tissue. A potential functional significance of such changes observed in optical tectum when considering wild fish contaminated in their natural habitat might be an impaired vision and therefore a lowered adaptability to their environment.

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“…In mice, exposure to methylmercury can induce tau hyperphosphorylation at specific sites mainly through c-Jun N-terminal kinase (JNK) pathway activation (Fujimura et al 2009). Data about the roles of other toxic metals in AD are sparse (Bush 2003;Shcherbatykh and Carpenter 2007;Stewart et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Higher Aluminum Concentration in Alzheimer’s Disease After Box–Cox Data Transformation

et al. 2011

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Evidence regarding the role of mercury and aluminum in the pathogenesis of Alzheimer's disease (AD) remains controversial. The aims of our project were to investigate the content of the selected metals in brain tissue samples and the use of a specific mathematical transform to eliminate the disadvantage of a strong positive skew in the original data distribution. In this study, we used atomic absorption spectrophotometry to determine mercury and aluminum concentrations in the hippocampus and associative visual cortex of 29 neuropathologically confirmed AD and 27 age-matched controls. The Box-Cox data transformation was used for statistical evaluation. AD brains had higher mean aluminum concentrations in the hippocampus than controls (0.357 vs. 0.090 μg/g; P = 0.039) after data transformation. Results for mercury were not significant. Original data regarding microelement concentrations are heavily skewed and do not pass the normality test in general. A Box-Cox transformation can eliminate this disadvantage and allow parametric testing.

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Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of the c-jun-N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mouse brain

Cited by 100 publications

References 34 publications

Methylmercury induces CCL2 expression through activation of NF-κB in human 1321N1 astrocytes

Methylmercury induces CCL2 expression through activation of NF-κB in human 1321N1 astrocytes

Effects of dietary methylmercury on the zebrafish brain: histological, mitochondrial, and gene transcription analyses

Higher Aluminum Concentration in Alzheimer’s Disease After Box–Cox Data Transformation

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