title: Genistein alleviates lead-induced neurotoxicity in vitro and in vivo: Involvement of multiple signaling pathways.
abstract: Lead (Pb) is a ubiquitous environmental and industrial pollutant. It induces neurotoxicity and cell death by disrupting the pro- and anti-oxidative balance; however, the mechanisms of its toxicity have yet to be fully understood. The soy-derived isoflavonoid, genistein (GEN), was reported to possess neuroprotective and antioxidative properties. The present study investigated the molecular mechanisms of Pb-induced neurotoxicity in vivo and in vitro, addressing the efficacy of GEN in protecting against Pb-induced toxicity. Pb exposure was associated with reduction of cell viability and cell apoptosis, concomitant with reactive oxygen species (ROS) generation in vitro, and pre-treatment with GEN markedly ameliorated the Pb-induced oxidative injury by increasing the expression of key antioxidant enzymes and the antioxidant transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2). Next, PKC-α activation was found after Pb exposure in vitro and pretreatment with GEN attenuated Pb-induced ROS generation by PKC-α inhibition. MAPK-NF-κB activation triggered by Pb was also inhibited by GEN. In summary, our study establishes that GEN alleviates Pb-induced impairment in spatial memory, and reduces cell apoptosis caused by Pb exposure and GEN protects neurons from Pb-induced neurotoxicity by downstream activation of antioxidant and anti-apoptotic pathways via regulation of Nrf2 and MAPK-NF-κB signaling.
authors.affiliation: Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Su
authors.affiliation: Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Siwang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Vanderbilt University Medical Center, Nashville.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Zipeng
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Diya
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China. Electronic address: jy_chen@fmmu.edu.cn.
authors.forename: Jiangyuan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China. Electronic address: luowenj@fmmu.edu.cn.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Luo
mesh_terms: D000818:Animals; D008297:Male; D051381:Rats; D000111:Acetylcysteine / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000627:therapeutic use; D019833:Genistein / Q000627:therapeutic use; D020287:In Situ Nick-End Labeling; D007854:Lead / Q000633:toxicity; D018782:Maze Learning / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000209:etiology; D016716:PC12 Cells / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism
chemical_list: D000111:Acetylcysteine; D002374:Catalase; D016166:Free Radical Scavengers; D019833:Genistein; D007854:Lead; D020929:Mitogen-Activated Protein Kinase Kinases; D018696:Neuroprotective Agents; D011493:Protein Kinase C; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat
keywords: Apoptosis; Genistein; Lead; MAPKs; NF-κB; Nrf2; Oxidative stress