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Scientific Reports Sep 2015We demonstrate the role of molecular switching of TrkA/p75(NTR) signaling cascade in organophosphate pesticide-Monocrotophos (MCP) induced neurotoxicity in stem cell...
We demonstrate the role of molecular switching of TrkA/p75(NTR) signaling cascade in organophosphate pesticide-Monocrotophos (MCP) induced neurotoxicity in stem cell derived cholinergic neurons and in rat brain. Our in-silico studies reveal that MCP followed the similar pattern of binding as staurosporine and AG-879 (known inhibitors of TrkA) with TrkA protein (PDB ID: 4AOJ) at the ATP binding sites. This binding of MCP to TrkA led to the conformational change in this protein and triggers the cell death cascades. The in-silico findings are validated by observing the down regulated levels of phosphorylated TrkA and its downstream molecules viz., pERK1/2, pAkt and pCREB in MCP-exposed cells. We observe that these MCP induced alterations in pTrkA and downstream signaling molecules are found to be associated with apoptosis and injury to neurons. The down-regulation of TrkA could be linked to increased p75(NTR). The in-vitro studies could be correlated in the rat model. The switching of TrkA/p75(NTR) signaling plays a central role in MCP-induced neural injury in rBNSCs and behavioral changes in exposed rats. Our studies significantly advance the understanding of the switching of TrkA/p75(NTR) that may pave the way for the application of TrkA inducer/p75(NTR) inhibitor for potential therapeutic intervention in various neurodegenerative disorders.
Topics: Animals; Apoptosis; Behavior, Animal; Brain; Cell Differentiation; Cells, Cultured; Cholinesterase Inhibitors; Insecticides; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Monocrotophos; Nerve Tissue Proteins; Neural Stem Cells; Neurons; Rats; Receptor, trkA; Receptors, Growth Factor; Receptors, Nerve Growth Factor; Signal Transduction; Structure-Activity Relationship
PubMed: 26370177
DOI: 10.1038/srep14038 -
PloS One 2014Our recent study showed that monocrotophos (MCP) pesticide disrupted the hypothalamic-pituitary-thyroid (HPT) axis in male goldfish (Carassius auratus); however, the...
Monocrotophos pesticide decreases the plasma levels of total 3,3',5-triiodo-l-thyronine and alters the expression of genes associated with the thyroidal axis in female goldfish (Carassius auratus).
Our recent study showed that monocrotophos (MCP) pesticide disrupted the hypothalamic-pituitary-thyroid (HPT) axis in male goldfish (Carassius auratus); however, the effects of MCP on the thyroid system in female goldfish are remain unclear. In the present study, plasma thyroid hormone (TH) and thyroid-stimulating hormone (TSH) levels were evaluated in female goldfish exposed to 0.01, 0.10, and 1.00 mg/L of 40% MCP-based pesticide for 21 days in a semi-static exposure system. Expression profiles of HPT axis-responsive genes, including transthyretin (ttr), deiodinases (d1, d2, and d3), tshβ, thyrotropin-releasing hormone (trh), and corticotrophin-releasing hormone (crh), were determined. The results indicated that MCP decreased the plasma levels of total 3,3',5-triiodo-l-thyronine (TT3) and the ratio of TT3 to total 3,3',5,5'-l-thyroxine (TT4), and induced alternative expression of TH-related genes. Exposure to 0.01 and 0.10 mg/L MCP pesticide resulted in the up-regulation of ttr mRNA. The reduction of plasma TT3 levels was partly attributed to an increase in the metabolism of T3 in the liver, as revealed by the highly elevated hepatic d1 and d3 mRNA levels in the MCP treatment groups, and the expression of hepatic d3 showed a negative correlation with the plasma TT3/TT4 levels in females. Moreover, the plasma TSH levels were lower in females exposed to 0.01 and 0.10 mg/L MCP pesticide, whereas the up-regulation of tshβ mRNA levels was compensated by the decreased plasma TT3 levels. These results indicated that MCP had the potential to influence several pathways of HPT axis homeostasis in female goldfish.
Topics: Animals; Brain; Corticotropin-Releasing Hormone; Female; Goldfish; Iodide Peroxidase; Kidney; Liver; Monocrotophos; Pesticides; Prealbumin; RNA, Messenger; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine
PubMed: 25268935
DOI: 10.1371/journal.pone.0108972