title: Cypermethrin induces astrocyte damage: role of aberrant Ca(2+), ROS, JNK, P38, matrix metalloproteinase 2 and migration related reelin protein.
abstract: Cypermethrin is a synthetic type II pyrethroid, derived from a natural pyrethrin of the chrysanthemum plant. Cypermethrin-mediated neurotoxicity is well studied; however, relatively less is known of its effect on astrocyte development and migration. Astrocytes are the major components of blood brain barrier (BBB), and astrocyte damage along with BBB dysfunction impair the tight junction (TJ) proteins resulting in altered cell migration and neurodegeneration. Here, we studied the mechanism of cypermethin mediated rat astrocyte damage and BBB disruption, and determined any change in expression of proteins associated with cell migration. Through MTT assay we found that cypermethrin reduced viability of cultured rat astrocytes. Immunolabelling with astrocyte marker, glial fibrillary acidic protein, revealed alteration in astrocyte morphology. The astrocytes demonstrated an enhanced release of intracellular Ca(++) and ROS, and up-regulation in p-JNK and p-P38 levels in a time-dependent manner. Cypermethrin disrupted the BBB (in vivo) in developing rats and attenuated the expression of the extracellular matrix molecule (ECM) and claudin-5 in cultured astrocytes. We further observed an augmentation in the levels of matrix metalloproteinase 2 (MMP2), known to modulate cellular migration and disrupt the developmental ECM and BBB. We observed an increase in the levels of reelin, involved in cell migration, in cultured rat astrocytes. The reelin receptor, α3β1integrin, and a mammalian cytosolic protein Disabled1 (Dab1) were also up-regulated. Overall, our study demonstrates that cypermethrin induces astrocyte injury via modulation in Ca(++), ROS, JNK and P38 pathways, which may alter MMP expression and reelin dependent astrocyte migration during brain development.
authors.affiliation: Department of Biosciences, Integral University, Lucknow 226026, India; Developmental Toxicology Division, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, India. Electronic address: mauryashailendra001@gmail.com.
authors.forename: Shailendra Kumar
authors.initials: SK
authors.lastname: Maurya
authors.affiliation: Developmental Toxicology Division, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, India.
authors.forename: Juhi
authors.initials: J
authors.lastname: Mishra
authors.affiliation: In vitro Toxicology Laboratory, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, India.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Tripathi
authors.affiliation: Department of Biosciences, Integral University, Lucknow 226026, India.
authors.forename: Rolee
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Bioengineering, Integral University, Lucknow 226026, India.
authors.forename: Mohammed Haris
authors.initials: MH
authors.lastname: Siddiqui
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010575:Pesticides / Q000633:toxicity*; D011722:Pyrethrins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D010575:Pesticides; D011722:Pyrethrins; D017382:Reactive Oxygen Species; D000091042:Reelin Protein; C000717129:Reln protein, rat; C017160:cypermethrin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D012697:Serine Endopeptidases; D020778:Matrix Metalloproteinase 2; D002118:Calcium
keywords: Astrocyte; Cell migration; Extracellular matrix; Pesticide; Toxic