{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:32:03Z","timestamp":1793316723187,"version":"4.5.0"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T00:00:00Z","timestamp":1620604800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T00:00:00Z","timestamp":1620604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K16345"],"award-info":[{"award-number":["19K16345"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15H05714"],"award-info":[{"award-number":["15H05714"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19H04276"],"award-info":[{"award-number":["19H04276"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We recently found that tumor necrosis factor-\u03b1 (TNF-\u03b1) may be involved in neuronal cell death induced by methylmercury in the mouse brain. Here, we examined the cells involved in the induction of TNF-\u03b1 expression by methylmercury in the mouse brain by in situ hybridization. TNF-\u03b1-expressing cells were found throughout the brain and were identified as microglia by immunostaining for ionized calcium binding adaptor molecule 1 (Iba1). Methylmercury induced TNF-\u03b1 expression in mouse primary microglia and mouse microglial cell line BV2. Knockdown of apoptosis signal-regulating kinase 1 (ASK1), an inflammatory cytokine up-regulator that is responsible for reactive oxygen species (ROS), decreased methylmercury-induced TNF-\u03b1 expression through decreased phosphorylation of p38 MAP kinase in BV2 cells. Suppression of methylmercury-induced reactive oxygen species (ROS) by antioxidant treatment largely abolished the induction of TNF-\u03b1 expression and phosphorylation of p38 by methylmercury in BV2 cells. Finally, in mouse brain slices, the TNF-\u03b1 antagonist (WP9QY) inhibited neuronal cell death induced by methylmercury, as did the p38 inhibitor SB203580 and liposomal clodronate (a microglia-depleting agent). These results indicate that methylmercury induces mitochondrial ROS that are involved in activation of the ASK1\/p38 pathway in microglia and that this is associated with induction of TNF-\u03b1 expression and neuronal cell death.<\/jats:p>","DOI":"10.1038\/s41598-021-89210-7","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T06:04:16Z","timestamp":1620626656000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Methylmercury induces neuronal cell death by inducing TNF-\u03b1 expression through the ASK1\/p38 signaling pathway in microglia"],"prefix":"10.1038","volume":"11","author":[{"given":"Takashi","family":"Toyama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Hoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Noguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiro","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Matsuzawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Naganuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gi-Wook","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"89210_CR1","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1042\/BJ20020841","volume":"367","author":"TA Simmons-Willis","year":"2002","unstructured":"Simmons-Willis, T. A., Koh, A. S., Clarkson, T. W. & Ballatori, N. Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem. J. 367, 239\u2013246. https:\/\/doi.org\/10.1042\/BJ20020841 (2002).","journal-title":"Biochem. J."},{"key":"89210_CR2","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1002\/tera.1420180216","volume":"18","author":"M Harada","year":"1978","unstructured":"Harada, M. Congenital Minamata disease: intrauterine methylmercury poisoning. Teratology 18, 285\u2013288. https:\/\/doi.org\/10.1002\/tera.1420180216 (1978).","journal-title":"Teratology"},{"key":"89210_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3109\/10408449509089885","volume":"25","author":"M Harada","year":"1995","unstructured":"Harada, M. Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit. Rev. Toxicol. 25, 1\u201324. https:\/\/doi.org\/10.3109\/10408449509089885 (1995).","journal-title":"Crit. Rev. Toxicol."},{"key":"89210_CR4","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.ntt.2005.12.009","volume":"28","author":"CS Roegge","year":"2006","unstructured":"Roegge, C. S. & Schantz, S. L. Motor function following developmental exposure to PCBS and\/or MEHG. Neurotoxicol. Teratol. 28, 260\u2013277. https:\/\/doi.org\/10.1016\/j.ntt.2005.12.009 (2006).","journal-title":"Neurotoxicol. Teratol."},{"key":"89210_CR5","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1289\/ehp.1408554","volume":"123","author":"JL Jacobson","year":"2015","unstructured":"Jacobson, J. L., Muckle, G., Ayotte, P., Dewailly, E. & Jacobson, S. W. Relation of prenatal methylmercury exposure from environmental sources to childhood IQ. Environ. Health Perspect. 123, 827\u2013833. https:\/\/doi.org\/10.1289\/ehp.1408554 (2015).","journal-title":"Environ. Health Perspect."},{"key":"89210_CR6","doi-asserted-by":"publisher","first-page":"49","DOI":"10.3390\/toxics6030049","volume":"6","author":"N Tatsuta","year":"2018","unstructured":"Tatsuta, N., Nakai, K., Sakamoto, M., Murata, K. & Satoh, H. Methylmercury exposure and developmental outcomes in Tohoku study of child development at 18 months of age. Toxics 6, 49. https:\/\/doi.org\/10.3390\/toxics6030049 (2018).","journal-title":"Toxics"},{"issue":"Suppl 2","key":"89210_CR7","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1289\/ehp.96104s2367","volume":"104","author":"C Watanabe","year":"1996","unstructured":"Watanabe, C. & Satoh, H. Evolution of our understanding of methylmercury as a health threat. Environ. Health Perspect. 104(Suppl 2), 367\u2013379. https:\/\/doi.org\/10.1289\/ehp.96104s2367 (1996).","journal-title":"Environ. Health Perspect."},{"key":"89210_CR8","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.3389\/fimmu.2020.01416","volume":"11","author":"A Matejuk","year":"2020","unstructured":"Matejuk, A. & Ransohoff, R. M. Crosstalk between astrocytes and microglia: an overview. Front. Immunol. 11, 1416. https:\/\/doi.org\/10.3389\/fimmu.2020.01416 (2020).","journal-title":"Front. Immunol."},{"key":"89210_CR9","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.brainresrev.2004.12.018","volume":"48","author":"D Garcia-Ovejero","year":"2005","unstructured":"Garcia-Ovejero, D., Azcoitia, I., Doncarlos, L. L., Melcangi, R. C. & Garcia-Segura, L. M. Glia-neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones. Brain Res. Brain Res. Rev. 48, 273\u2013286. https:\/\/doi.org\/10.1016\/j.brainresrev.2004.12.018 (2005).","journal-title":"Brain Res. Brain Res. Rev."},{"key":"89210_CR10","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/978-3-319-40764-7_4","volume":"949","author":"R von Bernhardi","year":"2016","unstructured":"von Bernhardi, R., Heredia, F., Salgado, N. & Munoz, P. Microglia function in the normal brain. Adv. Exp. Med. Biol. 949, 67\u201392. https:\/\/doi.org\/10.1007\/978-3-319-40764-7_4 (2016).","journal-title":"Adv. Exp. Med. Biol."},{"key":"89210_CR11","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature21029","volume":"541","author":"SA Liddelow","year":"2017","unstructured":"Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481\u2013487. https:\/\/doi.org\/10.1038\/nature21029 (2017).","journal-title":"Nature"},{"key":"89210_CR12","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1111\/bph.13139","volume":"173","author":"R Orihuela","year":"2016","unstructured":"Orihuela, R., McPherson, C. A. & Harry, G. J. Microglial M1\/M2 polarization and metabolic states. Br. J. Pharmacol. 173, 649\u2013665. https:\/\/doi.org\/10.1111\/bph.13139 (2016).","journal-title":"Br. J. Pharmacol."},{"key":"89210_CR13","doi-asserted-by":"publisher","first-page":"306","DOI":"10.3389\/fncel.2018.00306","volume":"12","author":"L Zhang","year":"2018","unstructured":"Zhang, L., Zhang, J. & You, Z. Switching of the microglial activation phenotype is a possible treatment for depression disorder. Front. Cell Neurosci. 12, 306. https:\/\/doi.org\/10.3389\/fncel.2018.00306 (2018).","journal-title":"Front. Cell Neurosci."},{"key":"89210_CR14","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1093\/toxsci\/kfr252","volume":"125","author":"D Godefroy","year":"2012","unstructured":"Godefroy, D. et al. The chemokine CCL2 protects against methylmercury neurotoxicity. Toxicol. Sci. 125, 209\u2013218. https:\/\/doi.org\/10.1093\/toxsci\/kfr252 (2012).","journal-title":"Toxicol. Sci."},{"key":"89210_CR15","doi-asserted-by":"publisher","first-page":"e57898","DOI":"10.1371\/journal.pone.0057898","volume":"8","author":"Y Noguchi","year":"2013","unstructured":"Noguchi, Y. et al. Astrocytes protect neurons against methylmercury via ATP\/P2Y(1) receptor-mediated pathways in astrocytes. PLoS ONE 8, e57898. https:\/\/doi.org\/10.1371\/journal.pone.0057898 (2013).","journal-title":"PLoS ONE"},{"key":"89210_CR16","doi-asserted-by":"publisher","first-page":"4329","DOI":"10.1038\/srep04329","volume":"4","author":"Y Shinozaki","year":"2014","unstructured":"Shinozaki, Y. et al. Microglia trigger astrocyte-mediated neuroprotection via purinergic gliotransmission. Sci. Rep. 4, 4329. https:\/\/doi.org\/10.1038\/srep04329 (2014).","journal-title":"Sci. Rep."},{"key":"89210_CR17","doi-asserted-by":"publisher","first-page":"13899","DOI":"10.1038\/s41598-019-50377-9","volume":"9","author":"Y Ishihara","year":"2019","unstructured":"Ishihara, Y. et al. Neuroprotective activation of astrocytes by methylmercury exposure in the inferior colliculus. Sci. Rep. 9, 13899. https:\/\/doi.org\/10.1038\/s41598-019-50377-9 (2019).","journal-title":"Sci. Rep."},{"key":"89210_CR18","doi-asserted-by":"publisher","first-page":"36","DOI":"10.3390\/toxics6030036","volume":"6","author":"T Takahashi","year":"2018","unstructured":"Takahashi, T. et al. Chemokine CCL4 induced in mouse brain has a protective role against methylmercury toxicity. Toxics 6, 36. https:\/\/doi.org\/10.3390\/toxics6030036 (2018).","journal-title":"Toxics"},{"key":"89210_CR19","doi-asserted-by":"publisher","first-page":"38294","DOI":"10.1038\/srep38294","volume":"6","author":"M Iwai-Shimada","year":"2016","unstructured":"Iwai-Shimada, M. et al. Methylmercury induces the expression of TNF-alpha selectively in the brain of mice. Sci. Rep. 6, 38294. https:\/\/doi.org\/10.1038\/srep38294 (2016).","journal-title":"Sci. Rep."},{"key":"89210_CR20","doi-asserted-by":"publisher","first-page":"549","DOI":"10.2131\/jts.44.549","volume":"44","author":"Y Shinoda","year":"2019","unstructured":"Shinoda, Y. et al. Gene expression profiles in the dorsal root ganglia of methylmercury-exposed rats. J. Toxicol. Sci. 44, 549\u2013558. https:\/\/doi.org\/10.2131\/jts.44.549 (2019).","journal-title":"J. Toxicol. Sci."},{"key":"89210_CR21","doi-asserted-by":"publisher","first-page":"3261","DOI":"10.1038\/sj.onc.1202568","volume":"17","author":"SJ Baker","year":"1998","unstructured":"Baker, S. J. & Reddy, E. P. Modulation of life and death by the TNF receptor superfamily. Oncogene 17, 3261\u20133270. https:\/\/doi.org\/10.1038\/sj.onc.1202568 (1998).","journal-title":"Oncogene"},{"key":"89210_CR22","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1111\/imr.12541","volume":"277","author":"B Tummers","year":"2017","unstructured":"Tummers, B. & Green, D. R. Caspase-8: regulating life and death. Immunol. Rev. 277, 76\u201389. https:\/\/doi.org\/10.1111\/imr.12541 (2017).","journal-title":"Immunol. Rev."},{"key":"89210_CR23","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1007\/s10787-019-00580-x","volume":"27","author":"D Kaur","year":"2019","unstructured":"Kaur, D., Sharma, V. & Deshmukh, R. Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer\u2019s disease. Inflammopharmacology 27, 663\u2013677. https:\/\/doi.org\/10.1007\/s10787-019-00580-x (2019).","journal-title":"Inflammopharmacology"},{"key":"89210_CR24","doi-asserted-by":"publisher","first-page":"e97649","DOI":"10.1371\/journal.pone.0097649","volume":"9","author":"AO Dumont","year":"2014","unstructured":"Dumont, A. O., Goursaud, S., Desmet, N. & Hermans, E. Differential regulation of glutamate transporter subtypes by pro-inflammatory cytokine TNF-alpha in cortical astrocytes from a rat model of amyotrophic lateral sclerosis. PLoS ONE 9, e97649. https:\/\/doi.org\/10.1371\/journal.pone.0097649 (2014).","journal-title":"PLoS ONE"},{"key":"89210_CR25","first-page":"25","volume":"8","author":"E Tobinick","year":"2006","unstructured":"Tobinick, E., Gross, H., Weinberger, A. & Cohen, H. TNF-alpha modulation for treatment of Alzheimer\u2019s disease: A 6-month pilot study. MedGenMed 8, 25 (2006).","journal-title":"MedGenMed"},{"key":"89210_CR26","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev.pharmtox.48.113006.094606","volume":"48","author":"K Takeda","year":"2008","unstructured":"Takeda, K., Noguchi, T., Naguro, I. & Ichijo, H. Apoptosis signal-regulating kinase 1 in stress and immune response. Annu. Rev. Pharmacol. Toxicol. 48, 199\u2013225. https:\/\/doi.org\/10.1146\/annurev.pharmtox.48.113006.094606 (2008).","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"89210_CR27","doi-asserted-by":"publisher","first-page":"37033","DOI":"10.1074\/jbc.M506771200","volume":"280","author":"T Noguchi","year":"2005","unstructured":"Noguchi, T. et al. Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death. J. Biol. Chem. 280, 37033\u201337040. https:\/\/doi.org\/10.1074\/jbc.M506771200 (2005).","journal-title":"J. Biol. Chem."},{"key":"89210_CR28","doi-asserted-by":"publisher","first-page":"8152","DOI":"10.1128\/MCB.00227-07","volume":"27","author":"G Fujino","year":"2007","unstructured":"Fujino, G. et al. Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1. Mol. Cell Biol. 27, 8152\u20138163. https:\/\/doi.org\/10.1128\/MCB.00227-07 (2007).","journal-title":"Mol. Cell Biol."},{"key":"89210_CR29","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/ni1200","volume":"6","author":"A Matsuzawa","year":"2005","unstructured":"Matsuzawa, A. et al. ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat. Immunol. 6, 587\u2013592. https:\/\/doi.org\/10.1038\/ni1200 (2005).","journal-title":"Nat. Immunol."},{"key":"89210_CR30","doi-asserted-by":"publisher","first-page":"7657","DOI":"10.1074\/jbc.M708402200","volume":"283","author":"T Noguchi","year":"2008","unstructured":"Noguchi, T. et al. Requirement of reactive oxygen species-dependent activation of ASK1-p38 MAPK pathway for extracellular ATP-induced apoptosis in macrophage. J. Biol. Chem. 283, 7657\u20137665. https:\/\/doi.org\/10.1074\/jbc.M708402200 (2008).","journal-title":"J. Biol. Chem."},{"key":"89210_CR31","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3390\/ijms18010205","volume":"18","author":"Y Hirata","year":"2017","unstructured":"Hirata, Y., Takahashi, M., Morishita, T., Noguchi, T. & Matsuzawa, A. Post-translational modifications of the TAK1-TAB complex. Int. J. Mol. Sci. 18, 205. https:\/\/doi.org\/10.3390\/ijms18010205 (2017).","journal-title":"Int. J. Mol. Sci."},{"key":"89210_CR32","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1038\/cdd.2014.123","volume":"21","author":"SR Mihaly","year":"2014","unstructured":"Mihaly, S. R., Ninomiya-Tsuji, J. & Morioka, S. TAK1 control of cell death. Cell Death Differ. 21, 1667\u20131676. https:\/\/doi.org\/10.1038\/cdd.2014.123 (2014).","journal-title":"Cell Death Differ."},{"key":"89210_CR33","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1002\/iub.1078","volume":"64","author":"L Dai","year":"2012","unstructured":"Dai, L., Aye Thu, C., Liu, X. Y., Xi, J. & Cheung, P. C. TAK1, more than just innate immunity. IUBMB Life 64, 825\u2013834. https:\/\/doi.org\/10.1002\/iub.1078 (2012).","journal-title":"IUBMB Life"},{"key":"89210_CR34","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1089\/08977150151071035","volume":"18","author":"LT Lau","year":"2001","unstructured":"Lau, L. T. & Yu, A. C. Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J. Neurotrauma 18, 351\u2013359. https:\/\/doi.org\/10.1089\/08977150151071035 (2001).","journal-title":"J. Neurotrauma"},{"key":"89210_CR35","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/1742-2094-5-46","volume":"5","author":"BH Clausen","year":"2008","unstructured":"Clausen, B. H. et al. Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. J. Neuroinflamm. 5, 46. https:\/\/doi.org\/10.1186\/1742-2094-5-46 (2008).","journal-title":"J. Neuroinflamm."},{"key":"89210_CR36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0169-328x(98)00040-0","volume":"57","author":"D Ito","year":"1998","unstructured":"Ito, D. et al. Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res. Mol. Brain Res. 57, 1\u20139. https:\/\/doi.org\/10.1016\/s0169-328x(98)00040-0 (1998).","journal-title":"Brain Res. Mol. Brain Res."},{"key":"89210_CR37","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/s0165-5728(85)80063-1","volume":"8","author":"LF Eng","year":"1985","unstructured":"Eng, L. F. Glial fibrillary acidic protein (GFAP): The major protein of glial intermediate filaments in differentiated astrocytes. J. Neuroimmunol. 8, 203\u2013214. https:\/\/doi.org\/10.1016\/s0165-5728(85)80063-1 (1985).","journal-title":"J. Neuroimmunol."},{"key":"89210_CR38","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1002\/emmm.201000103","volume":"2","author":"X Guo","year":"2010","unstructured":"Guo, X. et al. Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway. EMBO Mol. Med. 2, 504\u2013515. https:\/\/doi.org\/10.1002\/emmm.201000103 (2010).","journal-title":"EMBO Mol. Med."},{"key":"89210_CR39","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.intimp.2010.03.010","volume":"10","author":"KW Zeng","year":"2010","unstructured":"Zeng, K. W., Fu, H., Liu, G. X. & Wang, X. M. Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1\/IKK\/NF-kappa B and JNK\/p38 MAPK pathways. Int. Immunopharmacol. 10, 668\u2013678. https:\/\/doi.org\/10.1016\/j.intimp.2010.03.010 (2010).","journal-title":"Int. Immunopharmacol."},{"key":"89210_CR40","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1038\/nn.3531","volume":"16","author":"T Goldmann","year":"2013","unstructured":"Goldmann, T. et al. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat. Neurosci. 16, 1618\u20131626. https:\/\/doi.org\/10.1038\/nn.3531 (2013).","journal-title":"Nat. Neurosci."},{"key":"89210_CR41","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.freeradbiomed.2015.06.041","volume":"87","author":"A Ray","year":"2015","unstructured":"Ray, A., Sehgal, N., Karunakaran, S., Rangarajan, G. & Ravindranath, V. MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model. Free Radic. Biol. Med. 87, 312\u2013325. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2015.06.041 (2015).","journal-title":"Free Radic. Biol. Med."},{"key":"89210_CR42","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1089\/neu.2016.4486","volume":"34","author":"RE von Leden","year":"2017","unstructured":"von Leden, R. E., Yauger, Y. J., Khayrullina, G. & Byrnes, K. R. Central nervous system injury and nicotinamide adenine dinucleotide phosphate oxidase: Oxidative stress and therapeutic targets. J. Neurotrauma 34, 755\u2013764. https:\/\/doi.org\/10.1089\/neu.2016.4486 (2017).","journal-title":"J. Neurotrauma"},{"key":"89210_CR43","doi-asserted-by":"publisher","first-page":"F1144","DOI":"10.1152\/ajprenal.00221.2004","volume":"288","author":"M Satoh","year":"2005","unstructured":"Satoh, M. et al. NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. Am. J. Physiol. Renal. Physiol. 288, F1144-1152. https:\/\/doi.org\/10.1152\/ajprenal.00221.2004 (2005).","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"89210_CR44","doi-asserted-by":"publisher","first-page":"27540","DOI":"10.1074\/jbc.M114.604231","volume":"289","author":"S Kossmann","year":"2014","unstructured":"Kossmann, S. et al. Inflammatory monocytes determine endothelial nitric-oxide synthase uncoupling and nitro-oxidative stress induced by angiotensin II. J. Biol. Chem. 289, 27540\u201327550. https:\/\/doi.org\/10.1074\/jbc.M114.604231 (2014).","journal-title":"J. Biol. Chem."},{"key":"89210_CR45","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1161\/01.ATV.0000065234.70518.26","volume":"23","author":"H Mollnau","year":"2003","unstructured":"Mollnau, H. et al. Nebivolol prevents vascular NOS III uncoupling in experimental hyperlipidemia and inhibits NADPH oxidase activity in inflammatory cells. Arterioscler Thromb. Vasc. Biol. 23, 615\u2013621. https:\/\/doi.org\/10.1161\/01.ATV.0000065234.70518.26 (2003).","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"89210_CR46","doi-asserted-by":"publisher","first-page":"182","DOI":"10.3164\/jcbn.16-19","volume":"59","author":"Y Ishihara","year":"2016","unstructured":"Ishihara, Y., Tsuji, M., Kawamoto, T. & Yamazaki, T. Involvement of reactive oxygen species derived from mitochondria in neuronal injury elicited by methylmercury. J. Clin. Biochem. Nutr. 59, 182\u2013190. https:\/\/doi.org\/10.3164\/jcbn.16-19 (2016).","journal-title":"J. Clin. Biochem. Nutr."},{"key":"89210_CR47","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1093\/toxsci\/kfi224","volume":"87","author":"A Dreiem","year":"2005","unstructured":"Dreiem, A., Gertz, C. C. & Seegal, R. F. The effects of methylmercury on mitochondrial function and reactive oxygen species formation in rat striatal synaptosomes are age-dependent. Toxicol. Sci. 87, 156\u2013162. https:\/\/doi.org\/10.1093\/toxsci\/kfi224 (2005).","journal-title":"Toxicol. Sci."},{"key":"89210_CR48","doi-asserted-by":"publisher","first-page":"21528","DOI":"10.1038\/srep21528","volume":"6","author":"JY Lee","year":"2016","unstructured":"Lee, J. Y., Ishida, Y., Takahashi, T., Naganuma, A. & Hwang, G. W. Transport of pyruvate into mitochondria is involved in methylmercury toxicity. Sci. Rep. 6, 21528. https:\/\/doi.org\/10.1038\/srep21528 (2016).","journal-title":"Sci. Rep."},{"key":"89210_CR49","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1002\/art.22495","volume":"56","author":"H Saito","year":"2007","unstructured":"Saito, H. et al. A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti-tumor necrosis factor monoclonal antibody in murine collagen-induced arthritis. Arthritis Rheum. 56, 1164\u20131174. https:\/\/doi.org\/10.1002\/art.22495 (2007).","journal-title":"Arthritis Rheum."},{"key":"89210_CR50","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.nbd.2017.12.001","volume":"110","author":"I Waltl","year":"2018","unstructured":"Waltl, I. et al. Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis. Neurobiol. Dis. 110, 192\u2013205. https:\/\/doi.org\/10.1016\/j.nbd.2017.12.001 (2018).","journal-title":"Neurobiol. Dis."},{"key":"89210_CR51","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1002\/jnr.20562","volume":"81","author":"SU Kim","year":"2005","unstructured":"Kim, S. U. & de Vellis, J. Microglia in health and disease. J. Neurosci. Res. 81, 302\u2013313. https:\/\/doi.org\/10.1002\/jnr.20562 (2005).","journal-title":"J. Neurosci. Res."},{"key":"89210_CR52","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/0006-8993(89)91178-5","volume":"493","author":"SP Raps","year":"1989","unstructured":"Raps, S. P., Lai, J. C., Hertz, L. & Cooper, A. J. Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons. Brain Res. 493, 398\u2013401. https:\/\/doi.org\/10.1016\/0006-8993(89)91178-5 (1989).","journal-title":"Brain Res."},{"key":"89210_CR53","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1007\/s11064-013-1189-7","volume":"39","author":"C Petters","year":"2014","unstructured":"Petters, C. & Dringen, R. Comparison of primary and secondary rat astrocyte cultures regarding glucose and glutathione metabolism and the accumulation of iron oxide nanoparticles. Neurochem. Res. 39, 46\u201358. https:\/\/doi.org\/10.1007\/s11064-013-1189-7 (2014).","journal-title":"Neurochem. Res."},{"key":"89210_CR54","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.fct.2017.05.007","volume":"106","author":"M Zhao","year":"2017","unstructured":"Zhao, M., Lewis Wang, F. S., Hu, X., Chen, F. & Chan, H. M. Acrylamide-induced neurotoxicity in primary astrocytes and microglia: Roles of the Nrf2-ARE and NF-kappa B pathways. Food Chem. Toxicol. 106, 25\u201335. https:\/\/doi.org\/10.1016\/j.fct.2017.05.007 (2017).","journal-title":"Food Chem. Toxicol."},{"key":"89210_CR55","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1002\/glia.21153","volume":"59","author":"MW Ni","year":"2011","unstructured":"Ni, M. W. et al. Comparative study on the response of rat primary astrocytes and microglia to methylmercury toxicity. Glia 59, 810\u2013820. https:\/\/doi.org\/10.1002\/glia.21153 (2011).","journal-title":"Glia"},{"key":"89210_CR56","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1096\/fasebj.8.9.7516300","volume":"8","author":"WD Atchison","year":"1994","unstructured":"Atchison, W. D. & Hare, M. F. Mechanisms of methylmercury-induced neurotoxicity. FASEB J. 8, 622\u2013629. https:\/\/doi.org\/10.1096\/fasebj.8.9.7516300 (1994).","journal-title":"FASEB J."},{"key":"89210_CR57","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.immuni.2012.01.009","volume":"36","author":"K Shimada","year":"2012","unstructured":"Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401\u2013414. https:\/\/doi.org\/10.1016\/j.immuni.2012.01.009 (2012).","journal-title":"Immunity"},{"key":"89210_CR58","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1093\/toxsci\/kfy281","volume":"168","author":"M Fujimura","year":"2019","unstructured":"Fujimura, M., Usuki, F. & Nakamura, A. Fasudil, a rho-associated coiled coil-forming protein kinase inhibitor, recovers methylmercury-induced axonal degeneration by changing microglial phenotype in rats. Toxicol. Sci. 168, 126\u2013136. https:\/\/doi.org\/10.1093\/toxsci\/kfy281 (2019).","journal-title":"Toxicol. Sci."},{"key":"89210_CR59","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1161\/Atvbaha.108.166967","volume":"28","author":"QH Sun","year":"2008","unstructured":"Sun, Q. H. et al. Air pollution exposure potentiates hypertension through reactive oxygen species-mediated activation of Rho\/ROCK. Arterioscl. Throm. Vasc. 28, 1760\u20131766. https:\/\/doi.org\/10.1161\/Atvbaha.108.166967 (2008).","journal-title":"Arterioscl. Throm. Vasc."},{"key":"89210_CR60","doi-asserted-by":"publisher","first-page":"H1495","DOI":"10.1152\/ajpheart.01006.2003","volume":"287","author":"LM Jin","year":"2004","unstructured":"Jin, L. M., Ying, Z. K. & Webb, R. C. Activation of Rho\/Rho kinase signaling pathway by reactive oxygen species in rat aorta. Am. J. Physiol. Heart C 287, H1495\u2013H1500. https:\/\/doi.org\/10.1152\/ajpheart.01006.2003 (2004).","journal-title":"Am. J. Physiol. Heart C"},{"key":"89210_CR61","doi-asserted-by":"publisher","first-page":"5676","DOI":"10.1074\/jbc.M008787200","volume":"276","author":"WF Waas","year":"2001","unstructured":"Waas, W. F., Lo, H. H. & Dalby, K. N. The kinetic mechanism of the dual phosphorylation of the ATF2 transcription factor by p38 mitogen-activated protein (MAP) kinase alpha. Implications for signal\/response profiles of MAP kinase pathways. J. Biol. Chem. 276, 5676\u20135684. https:\/\/doi.org\/10.1074\/jbc.M008787200 (2001).","journal-title":"J. Biol. Chem."},{"key":"89210_CR62","doi-asserted-by":"publisher","first-page":"5601","DOI":"10.1093\/emboj\/18.20.5601","volume":"18","author":"KC Goh","year":"1999","unstructured":"Goh, K. C., Haque, S. J. & Williams, B. R. p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. EMBO J. 18, 5601\u20135608. https:\/\/doi.org\/10.1093\/emboj\/18.20.5601 (1999).","journal-title":"EMBO J."},{"key":"89210_CR63","doi-asserted-by":"publisher","first-page":"18842","DOI":"10.1074\/jbc.M500620200","volume":"280","author":"T Tanos","year":"2005","unstructured":"Tanos, T. et al. Phosphorylation of c-Fos by members of the p38 MAPK family. Role in the AP-1 response to UV light. J. Biol. Chem. 280, 18842\u201318852. https:\/\/doi.org\/10.1074\/jbc.M500620200 (2005).","journal-title":"J. Biol. Chem."},{"key":"89210_CR64","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1089\/jir.2005.25.707","volume":"25","author":"RW Ganster","year":"2005","unstructured":"Ganster, R. W., Guo, Z., Shao, L. & Geller, D. A. Differential effects of TNF-alpha and IFN-gamma on gene transcription mediated by NF-kappa B-Stat1 interactions. J. Interferon. Cytokine Res. 25, 707\u2013719. https:\/\/doi.org\/10.1089\/jir.2005.25.707 (2005).","journal-title":"J. Interferon. Cytokine Res."},{"key":"89210_CR65","doi-asserted-by":"publisher","first-page":"18432","DOI":"10.1074\/jbc.M906304199","volume":"275","author":"JH Steer","year":"2000","unstructured":"Steer, J. H., Kroeger, K. M., Abraham, L. J. & Joyce, D. A. Glucocorticoids suppress tumor necrosis factor-alpha expression by human monocytic THP-1 cells by suppressing transactivation through adjacent NF-kappa B and c-Jun-activating transcription factor-2 binding sites in the promoter. J. Biol. Chem. 275, 18432\u201318440. https:\/\/doi.org\/10.1074\/jbc.M906304199 (2000).","journal-title":"J. Biol. Chem."},{"key":"89210_CR66","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1097\/00004647-200007000-00007","volume":"20","author":"A Simi","year":"2000","unstructured":"Simi, A., Ingelman-Sundberg, M. & Tindberg, N. Neuroprotective agent chlomethiazole attenuates c-fos, c-jun, and AP-1 activation through inhibition of p38 MAP kinase. J. Cereb. Blood Flow Metab. 20, 1077\u20131088. https:\/\/doi.org\/10.1097\/00004647-200007000-00007 (2000).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"89210_CR67","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/s00403-008-0893-7","volume":"301","author":"MM Bashir","year":"2009","unstructured":"Bashir, M. M., Sharma, M. R. & Werth, V. P. TNF-alpha production in the skin. Arch. Dermatol. Res. 301, 87\u201391. https:\/\/doi.org\/10.1007\/s00403-008-0893-7 (2009).","journal-title":"Arch. Dermatol. Res."},{"key":"89210_CR68","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.mcn.2012.04.003","volume":"50","author":"GN Costa","year":"2012","unstructured":"Costa, G. N., Vindeirinho, J., Cavadas, C., Ambrosio, A. F. & Santos, P. F. Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose. Mol. Cell Neurosci. 50, 113\u2013123. https:\/\/doi.org\/10.1016\/j.mcn.2012.04.003 (2012).","journal-title":"Mol. Cell Neurosci."},{"key":"89210_CR69","doi-asserted-by":"publisher","first-page":"3844","DOI":"10.1016\/j.celrep.2019.05.087","volume":"27","author":"LJ Zhou","year":"2019","unstructured":"Zhou, L. J. et al. Microglia are indispensable for synaptic plasticity in the spinal dorsal horn and chronic pain. Cell Rep. 27, 3844-3859 e3846. https:\/\/doi.org\/10.1016\/j.celrep.2019.05.087 (2019).","journal-title":"Cell Rep."},{"key":"89210_CR70","doi-asserted-by":"publisher","first-page":"e975","DOI":"10.1038\/cddis.2013.503","volume":"4","author":"B Parajuli","year":"2013","unstructured":"Parajuli, B. et al. Oligomeric amyloid beta induces IL-1beta processing via production of ROS: implication in Alzheimer\u2019s disease. Cell Death Dis. 4, e975. https:\/\/doi.org\/10.1038\/cddis.2013.503 (2013).","journal-title":"Cell Death Dis."},{"key":"89210_CR71","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.3390\/molecules22081287","volume":"22","author":"JK Lee","year":"2017","unstructured":"Lee, J. K. & Kim, N. J. Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer\u2019s disease. Molecules 22, 1287. https:\/\/doi.org\/10.3390\/molecules22081287 (2017).","journal-title":"Molecules"},{"key":"89210_CR72","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.bbrc.2009.01.082","volume":"380","author":"K Koh","year":"2009","unstructured":"Koh, K., Cha, Y., Kim, S. & Kim, J. tBHQ inhibits LPS-induced microglial activation via Nrf2-mediated suppression of p38 phosphorylation. Biochem. Biophys. Res. Commun. 380, 449\u2013453. https:\/\/doi.org\/10.1016\/j.bbrc.2009.01.082 (2009).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"89210_CR73","doi-asserted-by":"publisher","first-page":"471","DOI":"10.2131\/jts.44.471","volume":"44","author":"T Hoshi","year":"2019","unstructured":"Hoshi, T. et al. Evaluation of M1-microglial activation by neurotoxic metals using optimized organotypic cerebral slice cultures. J. Toxicol. Sci. 44, 471\u2013479. https:\/\/doi.org\/10.2131\/jts.44.471 (2019).","journal-title":"J. Toxicol. Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89210-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89210-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89210-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T02:49:07Z","timestamp":1670035747000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89210-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,10]]},"references-count":73,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["89210"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-89210-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,10]]},"assertion":[{"value":"31 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9832"}}