title: Cypermethrin induces astrocyte apoptosis by the disruption of the autocrine/paracrine mode of epidermal growth factor receptor signaling.
abstract: Cypermethrin is reported to affect astrocytes in rat brain; however, its mechanism of action is obscure. Here, we observed an increase in apoptosis in the cortical astrocytes upon treatment of rats with cypermethrin. We then characterized the mechanism governing the apoptosis. Because the epidermal growth factor receptor (EGFR) signaling regulates the survival of astrocytes, we investigated the effect of cypermethrin on EGFR activation. The astrocytes exhibited an early and irreversible attenuation in the basal EGFR phosphorylation. Supportively, molecular docking studies revealed considerable homology in the docking mode of cypermethrin and the known EGFR inhibitors, erlotinib and AG1478, to the kinase domain of EGFR. Furthermore, treatment with cypermethrin demonstrated a downregulation in the intracellular and secreted levels of heparin-binding epidermal growth factor (HB-EGF), an EGFR ligand. AG1478 reduced the synthesis of HB-EGF, suggesting the dependence of HB-EGF on EGFR activation. In addition, a neutralizing antibody against HB-EGF diminished the basal EGFR levels, indicating ligand-dependent expression of EGFR. Likewise, cypermethrin caused irreversible suppression in the basal EGFR levels, which induced apoptosis in astrocytes. The apoptosis was prevented by exogenous HB-EGF. These data imply an autocrine/paracrine mode of action of HB-EGF-EGFR in astrocyte survival. Consequently, cypermethrin induced a mitochondria-mediated apoptosis, characterized by rise in Bax/Bcl-2 ratio and cleavage of caspase-9, -3, and -7, and the effect was prevented by HB-EGF. HB-EGF activated the extracellular signal-regulated kinases and AKT pathways that protected against apoptosis. Together, these data demonstrate that cypermethrin induces astrocyte apoptosis by disrupting the autocrine/paracrine mode of HB-EGF-EGFR signaling at two levels, irreversible loss of basal EGFR and downregulation of HB-EGF.
authors: Developmental Toxicology Division, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow-226001, India.
authors: Shailendra Kumar
authors: SK
authors: Maurya
authors: Asit
authors: A
authors: Rai
authors: Nagendra Kumar
authors: NK
authors: Rai
authors: Shreekant
authors: S
authors: Deshpande
authors: Rajeev
authors: R
authors: Jain
authors: Mohana Krishna Reddy
authors: MK
authors: Mudiam
authors: Yenamandra S
authors: YS
authors: Prabhakar
authors: Sanghamitra
authors: S
authors: Bandyopadhyay
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019898:Autocrine Communication / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D019899:Paracrine Communication / Q000187:drug effects*; D010766:Phosphorylation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011722:Pyrethrins / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011722:Pyrethrins; C017160:cypermethrin; C483803:Egfr protein, rat; D066246:ErbB Receptors