Acute exposure to lead acetate activates microglia and induces subsequent bystander neuronal death via caspase-3 activation
•We used mouse microglial BV-2 cells for inflammation studies upon Pb exposure.•Pb induces the phosphorylation of ERK and Akt pathways.•Pb leads to the phosphorylation and nuclear translocation of NF-kB.•BV-2 cells respond by secreting pro-inflammatory cyto-chemokines upon Pb exposure.•Pb-treated BV...
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description | •We used mouse microglial BV-2 cells for inflammation studies upon Pb exposure.•Pb induces the phosphorylation of ERK and Akt pathways.•Pb leads to the phosphorylation and nuclear translocation of NF-kB.•BV-2 cells respond by secreting pro-inflammatory cyto-chemokines upon Pb exposure.•Pb-treated BV-2 cells secrete factors that activate caspase-3 in N2a cells.
Lead is one of the major pollutants of environment and is highly toxic to the functioning of central nervous system (CNS). The chronic exposure of this heavy metal is debilitating to the functional behavior of an organism. Studies have shown that acute exposure to Pb can lead to glial activation and secretion of cyto-chemokines in both in vitro and in vivo models. However, the cellular source of secretion of these cyto-chemokines remains to be identified. Microglia are monocytes of the brain, and are primary source of cytokine secretion in the CNS. We hypothesized that microglia exposed to Pb can secrete cyto-chemokines, thereby resulting in subsequent neuronal death. Our studies show that stimulation of BV-2 mouse microglia with 10μМ dose of Pb resulted in up-regulation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) pathways, along with activation of an important transcription factor, nuclear factor-κB (NF-κB). Further, we found that the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) pro-inflammatory enzyme were increased in response to Pb exposure. Furthermore, treatment with conditioned media from Pb treated BV-2 cells lead to neuronal death in neuroblastoma cells, which potentially involved the activation of caspase-3 enzyme. In all, the current study brings forth critical involvement of microglial activation in mediating the neurotoxicity associated with lead exposure. |
doi_str_mv | 10.1016/j.neuro.2014.02.002 |
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Lead is one of the major pollutants of environment and is highly toxic to the functioning of central nervous system (CNS). The chronic exposure of this heavy metal is debilitating to the functional behavior of an organism. Studies have shown that acute exposure to Pb can lead to glial activation and secretion of cyto-chemokines in both in vitro and in vivo models. However, the cellular source of secretion of these cyto-chemokines remains to be identified. Microglia are monocytes of the brain, and are primary source of cytokine secretion in the CNS. We hypothesized that microglia exposed to Pb can secrete cyto-chemokines, thereby resulting in subsequent neuronal death. Our studies show that stimulation of BV-2 mouse microglia with 10μМ dose of Pb resulted in up-regulation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) pathways, along with activation of an important transcription factor, nuclear factor-κB (NF-κB). Further, we found that the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) pro-inflammatory enzyme were increased in response to Pb exposure. Furthermore, treatment with conditioned media from Pb treated BV-2 cells lead to neuronal death in neuroblastoma cells, which potentially involved the activation of caspase-3 enzyme. In all, the current study brings forth critical involvement of microglial activation in mediating the neurotoxicity associated with lead exposure.</description><identifier>ISSN: 0161-813X</identifier><identifier>EISSN: 1872-9711</identifier><identifier>DOI: 10.1016/j.neuro.2014.02.002</identifier><identifier>PMID: 24530660</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Analysis of Variance ; Animals ; Apoptosis ; Biological and medical sciences ; Caspase 3 - metabolism ; Cell Death - drug effects ; Cell Line, Transformed ; Cell Survival - drug effects ; Central nervous system ; Chemical and industrial products toxicology. Toxic occupational diseases ; COX-2 ; Culture Media, Conditioned - pharmacology ; Cyclooxygenase 2 - metabolism ; Cytokines - metabolism ; Dose-Response Relationship, Drug ; Lead ; MAP Kinase Kinase Kinase 5 - metabolism ; Medical sciences ; Metals and various inorganic compounds ; Mice ; Microglia ; Microglia - drug effects ; Molecular Weight ; Neurons - physiology ; NF-κB ; Organometallic Compounds - pharmacology ; Reactive Oxygen Species - metabolism ; Signal Transduction - drug effects ; Time Factors ; Toxicology</subject><ispartof>Neurotoxicology (Park Forest South), 2014-03, Vol.41, p.143-153</ispartof><rights>2014 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2014 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-9f1c52f0524a0edab8e6ec9e9e6dabe7af620563c43abfce2fcce86c47a9de2f3</citedby><cites>FETCH-LOGICAL-c422t-9f1c52f0524a0edab8e6ec9e9e6dabe7af620563c43abfce2fcce86c47a9de2f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neuro.2014.02.002$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28562374$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24530660$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kumawat, Kanhaiya Lal</creatorcontrib><creatorcontrib>Kaushik, Deepak Kumar</creatorcontrib><creatorcontrib>Goswami, Praveen</creatorcontrib><creatorcontrib>Basu, Anirban</creatorcontrib><title>Acute exposure to lead acetate activates microglia and induces subsequent bystander neuronal death via caspase-3 activation</title><title>Neurotoxicology (Park Forest South)</title><addtitle>Neurotoxicology</addtitle><description>•We used mouse microglial BV-2 cells for inflammation studies upon Pb exposure.•Pb induces the phosphorylation of ERK and Akt pathways.•Pb leads to the phosphorylation and nuclear translocation of NF-kB.•BV-2 cells respond by secreting pro-inflammatory cyto-chemokines upon Pb exposure.•Pb-treated BV-2 cells secrete factors that activate caspase-3 in N2a cells.
Lead is one of the major pollutants of environment and is highly toxic to the functioning of central nervous system (CNS). The chronic exposure of this heavy metal is debilitating to the functional behavior of an organism. Studies have shown that acute exposure to Pb can lead to glial activation and secretion of cyto-chemokines in both in vitro and in vivo models. However, the cellular source of secretion of these cyto-chemokines remains to be identified. Microglia are monocytes of the brain, and are primary source of cytokine secretion in the CNS. We hypothesized that microglia exposed to Pb can secrete cyto-chemokines, thereby resulting in subsequent neuronal death. Our studies show that stimulation of BV-2 mouse microglia with 10μМ dose of Pb resulted in up-regulation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) pathways, along with activation of an important transcription factor, nuclear factor-κB (NF-κB). Further, we found that the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) pro-inflammatory enzyme were increased in response to Pb exposure. Furthermore, treatment with conditioned media from Pb treated BV-2 cells lead to neuronal death in neuroblastoma cells, which potentially involved the activation of caspase-3 enzyme. In all, the current study brings forth critical involvement of microglial activation in mediating the neurotoxicity associated with lead exposure.</description><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Caspase 3 - metabolism</subject><subject>Cell Death - drug effects</subject><subject>Cell Line, Transformed</subject><subject>Cell Survival - drug effects</subject><subject>Central nervous system</subject><subject>Chemical and industrial products toxicology. Toxic occupational diseases</subject><subject>COX-2</subject><subject>Culture Media, Conditioned - pharmacology</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Cytokines - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Lead</subject><subject>MAP Kinase Kinase Kinase 5 - metabolism</subject><subject>Medical sciences</subject><subject>Metals and various inorganic compounds</subject><subject>Mice</subject><subject>Microglia</subject><subject>Microglia - drug effects</subject><subject>Molecular Weight</subject><subject>Neurons - physiology</subject><subject>NF-κB</subject><subject>Organometallic Compounds - pharmacology</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Time Factors</subject><subject>Toxicology</subject><issn>0161-813X</issn><issn>1872-9711</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9v1DAQxS0EotvCJ0BCviBxSfCfxEkOHKoKKFIlLiBxsybjCXiVdRbbWbXiy-N2t3DjZI_n98ZvHmOvpKilkObdtg60xqVWQja1ULUQ6gnbyL5T1dBJ-ZRtCiWrXurvZ-w8pa0Qsu3M8JydqabVwhixYb8vcc3E6Xa_pDUSzwufCRwHpAylAZj9oVwS33mMy4_ZA4fguA9uxfKa1jHRr5VC5uNdyqVFkT_4CjBzR5B_8kPRIKQ9JKr040S_hBfs2QRzopen84J9-_jh69V1dfPl0-ery5sKG6VyNUwSWzWJVjUgyMHYkyEcaCBTCupgMkq0RmOjYZyQ1IRIvcGmg8GVSl-wt8e5-7gUqynbnU9I8wyBljVZaTqj277t-4LqI1p2TSnSZPfR7yDeWSnsfep2ax-2s_epW6FsSb2oXp8-WMcdub-ax5gL8OYEQEKYpwgBffrH9a1RumsK9_7IUYnj4CnahJ4CkvORMFu3-P8a-QOl1qV3</recordid><startdate>20140301</startdate><enddate>20140301</enddate><creator>Kumawat, Kanhaiya Lal</creator><creator>Kaushik, Deepak Kumar</creator><creator>Goswami, Praveen</creator><creator>Basu, Anirban</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T2</scope><scope>7TK</scope><scope>7TV</scope><scope>7U2</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>20140301</creationdate><title>Acute exposure to lead acetate activates microglia and induces subsequent bystander neuronal death via caspase-3 activation</title><author>Kumawat, Kanhaiya Lal ; Kaushik, Deepak Kumar ; Goswami, Praveen ; Basu, Anirban</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-9f1c52f0524a0edab8e6ec9e9e6dabe7af620563c43abfce2fcce86c47a9de2f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Caspase 3 - metabolism</topic><topic>Cell Death - drug effects</topic><topic>Cell Line, Transformed</topic><topic>Cell Survival - drug effects</topic><topic>Central nervous system</topic><topic>Chemical and industrial products toxicology. Toxic occupational diseases</topic><topic>COX-2</topic><topic>Culture Media, Conditioned - pharmacology</topic><topic>Cyclooxygenase 2 - metabolism</topic><topic>Cytokines - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Lead</topic><topic>MAP Kinase Kinase Kinase 5 - metabolism</topic><topic>Medical sciences</topic><topic>Metals and various inorganic compounds</topic><topic>Mice</topic><topic>Microglia</topic><topic>Microglia - drug effects</topic><topic>Molecular Weight</topic><topic>Neurons - physiology</topic><topic>NF-κB</topic><topic>Organometallic Compounds - pharmacology</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Time Factors</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kumawat, Kanhaiya Lal</creatorcontrib><creatorcontrib>Kaushik, Deepak Kumar</creatorcontrib><creatorcontrib>Goswami, Praveen</creatorcontrib><creatorcontrib>Basu, Anirban</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Health and Safety Science Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Pollution Abstracts</collection><collection>Safety Science and Risk</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Neurotoxicology (Park Forest South)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumawat, Kanhaiya Lal</au><au>Kaushik, Deepak Kumar</au><au>Goswami, Praveen</au><au>Basu, Anirban</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acute exposure to lead acetate activates microglia and induces subsequent bystander neuronal death via caspase-3 activation</atitle><jtitle>Neurotoxicology (Park Forest South)</jtitle><addtitle>Neurotoxicology</addtitle><date>2014-03-01</date><risdate>2014</risdate><volume>41</volume><spage>143</spage><epage>153</epage><pages>143-153</pages><issn>0161-813X</issn><eissn>1872-9711</eissn><abstract>•We used mouse microglial BV-2 cells for inflammation studies upon Pb exposure.•Pb induces the phosphorylation of ERK and Akt pathways.•Pb leads to the phosphorylation and nuclear translocation of NF-kB.•BV-2 cells respond by secreting pro-inflammatory cyto-chemokines upon Pb exposure.•Pb-treated BV-2 cells secrete factors that activate caspase-3 in N2a cells.
Lead is one of the major pollutants of environment and is highly toxic to the functioning of central nervous system (CNS). The chronic exposure of this heavy metal is debilitating to the functional behavior of an organism. Studies have shown that acute exposure to Pb can lead to glial activation and secretion of cyto-chemokines in both in vitro and in vivo models. However, the cellular source of secretion of these cyto-chemokines remains to be identified. Microglia are monocytes of the brain, and are primary source of cytokine secretion in the CNS. We hypothesized that microglia exposed to Pb can secrete cyto-chemokines, thereby resulting in subsequent neuronal death. Our studies show that stimulation of BV-2 mouse microglia with 10μМ dose of Pb resulted in up-regulation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) pathways, along with activation of an important transcription factor, nuclear factor-κB (NF-κB). Further, we found that the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) pro-inflammatory enzyme were increased in response to Pb exposure. Furthermore, treatment with conditioned media from Pb treated BV-2 cells lead to neuronal death in neuroblastoma cells, which potentially involved the activation of caspase-3 enzyme. In all, the current study brings forth critical involvement of microglial activation in mediating the neurotoxicity associated with lead exposure.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>24530660</pmid><doi>10.1016/j.neuro.2014.02.002</doi><tpages>11</tpages></addata></record> |
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subjects | Analysis of Variance Animals Apoptosis Biological and medical sciences Caspase 3 - metabolism Cell Death - drug effects Cell Line, Transformed Cell Survival - drug effects Central nervous system Chemical and industrial products toxicology. Toxic occupational diseases COX-2 Culture Media, Conditioned - pharmacology Cyclooxygenase 2 - metabolism Cytokines - metabolism Dose-Response Relationship, Drug Lead MAP Kinase Kinase Kinase 5 - metabolism Medical sciences Metals and various inorganic compounds Mice Microglia Microglia - drug effects Molecular Weight Neurons - physiology NF-κB Organometallic Compounds - pharmacology Reactive Oxygen Species - metabolism Signal Transduction - drug effects Time Factors Toxicology |
title | Acute exposure to lead acetate activates microglia and induces subsequent bystander neuronal death via caspase-3 activation |
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