Journal Article

Cypermethrin Induces Astrocyte Apoptosis by the Disruption of the Autocrine/Paracrine Mode of Epidermal Growth Factor Receptor Signaling

Shailendra Kumar Maurya, Asit Rai, Nagendra Kumar Rai, Shreekant Deshpande, Rajeev Jain, Mohana Krishna Reddy Mudiam, Yenamandra S. Prabhakar and Sanghamitra Bandyopadhyay

in Toxicological Sciences

Volume 125, issue 2, pages 473-487
Published in print February 2012 | ISSN: 1096-6080
Published online November 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr303
Cypermethrin Induces Astrocyte Apoptosis by the Disruption of the Autocrine/Paracrine Mode of Epidermal Growth Factor Receptor Signaling

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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.

Keywords: autocrine/paracrine; phosphorylation; mitochondria; MAPK

Journal Article.  7525 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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