title: Tributyltin induces oxidative damage, inflammation and apoptosis via disturbance in blood-brain barrier and metal homeostasis in cerebral cortex of rat brain: an in vivo and in vitro study.
abstract: Tributyltin (TBT), a member of the organotin family, is primarily used for its biocidal activity. Persistent environmental levels of TBT pose threat to the ecosystem. Since neurotoxic influence of TBT remains elusive, we therefore, studied its effect on cerebral cortex of male Wistar rats. A single oral dose of Tributyltin-Chloride (TBTC) (10, 20, 30mg/kg) was administered and the animals were sacrificed on day 3 and day 7. Blood-brain barrier permeability remained disrupted significantly till day 7 with all the doses of TBTC. Pro-oxidant metal levels (Fe, Cu) were increased with a concomitant decrease in Zn. ROS generation was substantially raised resulting in oxidative damage (increased protein carbonylation and lipid peroxidation) with marked decline in tissue antioxidant status (GSH/GSSG levels). Protein expression studies indicated astrocyte activation, upregulation of inflammatory molecules (IL-6, Cox-2 and NF-κB) and simultaneous elevation in the apoptotic index (Bax/Bcl2). Neurodegeneration was evident by reduced neurofilament expression and increased calpain cleaved Tau levels. The in-vitro study demonstrated involvement of calcium and signaling molecules (p38), with downstream activation of caspase-3 and -8, and apoptotic cell death was evident by nuclear fragmentation, DNA laddering and Annexin V binding experiments. Ca(2+) inhibitors (BAPTA-AM, EGTA, and RR) and free radical scavengers (NAC and biliprotein [C-PC]) increased cell viability (MTT assay), signifying specific roles of Ca(2+) and ROS. Significance of p38 signaling was evaluated on pro-apoptotic proteins by using SB203580, a selective p38 inhibitor. Our data collectively illustrates that TBTC can disrupt BBB, induce oxidative stress, cause cell death and initiate neurodegeneration in rat brain.
authors.affiliation: Immunotoxicology Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, Lucknow 226001, India.
authors.forename: Sumonto
authors.initials: S
authors.lastname: Mitra
authors.forename: Ruchi
authors.initials: R
authors.lastname: Gera
authors.forename: Waseem A
authors.initials: WA
authors.lastname: Siddiqui
authors.forename: Shashi
authors.initials: S
authors.lastname: Khandelwal
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019216:Metals, Heavy / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D004785:Environmental Pollutants; D019216:Metals, Heavy; D017382:Reactive Oxygen Species; D014220:Trialkyltin Compounds; C011559:tributyltin
keywords: Apoptosis; Inflammation; Neurotoxicity; Oxidative damage; Tributyltin chloride