{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T04:44:16Z","timestamp":1792557856655,"version":"4.5.0"},"reference-count":99,"publisher":"American Chemical Society (ACS)","issue":"12","license":[{"start":{"date-parts":[[2017,12,29]],"date-time":"2017-12-29T00:00:00Z","timestamp":1514505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>As a ubiquitous environmental pollutant, methylmercury (MeHg) induces toxic effects in the nervous system, one of its main targets. However, the exact mechanisms of its neurotoxicity have not been fully elucidated. Hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1), a transcription factor, plays a crucial role in adaptive and cytoprotective responses in cells and is involved in cell survival, proliferation, apoptosis, inflammation, angiogenesis, glucose metabolism, erythropoiesis, and other physiological activities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives:<\/jats:title>\n                    <jats:p>The aim of this study was to explore the role of HIF-1\u03b1 in response to acute MeHg exposure in rat brain and primary cultured astrocytes to improve understanding of the mechanisms of MeHg-induced neurotoxicity and the development of effective neuroprotective strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Primary rat astrocytes were treated with MeHg (0\u201310\u03bcM) for 0.5h. Cell proliferation and cytotoxicity were assessed with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl diphenyltetrazolium bromide (MTT) assay and a lactate dehydrogenase (LDH) release assay, respectively. Reactive oxygen species (ROS) levels were analyzed to assess the level of oxidative stress using 2\u2032,7\u2032-dichlorofluorescin diacetate (DCFH-DA) fluorescence. HIF-1\u03b1, and its downstream proteins, glucose transporter 1 (GLUT-1), erythropoietin (EPO), and vascular endothelial growth factor A (VEGF-A) were analyzed by means of Western blotting. Real-time PCR was used to detect the expression of HIF-1\u03b1 mRNA. Pretreatment with protein synthesis inhibitor (CHX), proteasome inhibitor (MG132), or proline hydroxylase inhibitor (DHB) were applied to explore the possible mechanisms of HIF-1\u03b1 inhibition by MeHg. To investigate the role of HIF-1\u03b1 in MeHg-induced neurotoxicity, cobalt chloride (CoCl2), 2-methoxyestradiol (2-MeOE2), small interfering RNA (siRNA) transfection and adenovirus overexpression were used. Pretreatment with N-acetyl-L-cysteine (NAC) and vitamin E (Trolox) were used to investigate the putative role of oxidative stress in MeHg-induced alterations in HIF-1\u03b1 levels. The expression of HIF-1\u03b1 and related downstream proteins was detected in adult rat brain exposed to MeHg (0\u201310mg\/kg) for 0.5h\u00a0in\u00a0vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>MeHg caused lower cell proliferation and higher cytotoxicity in primary rat astrocytes in a time- and concentration-dependent manner. In comparison with the control cells, exposure to 10\u03bcM MeHg for 0.5h significantly inhibited the expression of astrocytic HIF-1\u03b1, and the downstream genes GLUT-1, EPO, and VEGF-A (p&amp;lt;0.05), in the absence of a significant decrease in HIF-1\u03b1 mRNA levels. When protein synthesis was inhibited by CHX, MeHg promoted the degradation rate of HIF-1\u03b1. MG132 and DHB significantly blocked the MeHg-induced decrease in HIF-1\u03b1 expression (p&amp;lt;0.05). Overexpression of HIF-1\u03b1 significantly attenuated the decline in MeHg-induced cell proliferation, whereas the inhibition of HIF-1\u03b1 significantly increased the decline in cell proliferation (p&amp;lt;0.05). NAC and Trolox, two established antioxidants, reversed the MeHg-induced decline in HIF-1\u03b1 protein levels and the decrease in cell proliferation (p&amp;lt;0.05). MeHg suppressed the expression of HIF-1\u03b1 and related downstream target proteins in adult rat brain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion:<\/jats:title>\n                    <jats:p>MeHg induced a significant reduction in HIF-1\u03b1 protein by activating proline hydroxylase (PHD) and the ubiquitin proteasome system (UPS) in primary rat astrocytes. Additionally, ROS scavenging by antioxidants played a neuroprotective role via increasing HIF-1\u03b1 expression in response to MeHg toxicity. Moreover, we established that up-regulation of HIF-1\u03b1 might serve to mitigate the acute toxicity of MeHg in astrocytes, affording a novel therapeutic target for future exploration. https:\/\/doi.org\/10.1289\/EHP5139<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1289\/ehp5139","type":"journal-article","created":{"date-parts":[[2019,12,18]],"date-time":"2019-12-18T09:16:15Z","timestamp":1576660575000},"source":"Crossref","is-referenced-by-count":58,"title":["Acute Methylmercury Exposure and the Hypoxia-Inducible Factor-1\u03b1 Signaling Pathway under Normoxic Conditions in the Rat Brain and Astrocytes\n                    <i>in Vitro<\/i>"],"prefix":"10.1021","volume":"127","author":[{"given":"Jie","family":"Chang","sequence":"first","affiliation":[{"name":"Jiangsu University Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, , Zhenjiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bobo","family":"Yang","sequence":"additional","affiliation":[{"name":"Jiangsu University Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, , Zhenjiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Jiangsu University Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, , Zhenjiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changsheng","family":"Yin","sequence":"additional","affiliation":[{"name":"Jiangsu University Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, , Zhenjiang,","place":["China"]},{"name":"Jiangsu University Institute of Life Sciences, , Zhenjiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu University Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, , Zhenjiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Qian","sequence":"additional","affiliation":[{"name":"Jiangsu University Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, , Zhenjiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangwei","family":"Xing","sequence":"additional","affiliation":[{"name":"Jiangsu University Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, , Zhenjiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu University Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, , Zhenjiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangsu University Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, , Zhenjiang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Public Health, Fudan University Department of Occupational Health and Toxicology, , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da","family":"Chen","sequence":"additional","affiliation":[{"name":"Jinan University School 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