title: Altered canonical hedgehog-gli signalling axis in pesticide-induced bone marrow aplasia mouse model.
abstract: The mechanistic interplay between pesticide exposure and development of marrow aplasia is not yet well established but there are indices that chronic pesticide exposure in some instances causes marrow aplasia like haematopoietic degenerative condition in human beings. Canonical Hedgehog (Hh) signalling has multiple roles in a wide range of developmental processes, including haematopoiesis. The present study was designed to explore the status of four important components of the canonical Hedgehog signalling cascade, the Sonic Hedgehog (Shh), Ptch1, Smo, and Gli1, in a mouse model of chronic pesticide-induced bone marrow aplasia. We used 5 % aqueous mixture of pesticides (chlorpyriphos, prophenophos, cypermethrin, alpha-methrin, and hexaconazole) for inhalation and dermal exposure of 6 hours per day and 5 days a week up to 90 days. Murine bone marrow aplasia related to chronic pesticide treatment was confirmed primarily by haemogram, bone marrow cellularity, short term bone marrow explant culture for cellular kinetics, bone marrow smear, and fl ow cytometric Lin-Sca-1+C-kit+ extracellular receptor expression pattern. Later, components of hedgehog signalling were analysed in the bone marrow of both control and pesticide-treated aplastic groups of animals. The results depicted pancytopenic feature of peripheral blood, developmental anomaly of neutrophils, depression of primitive stem and progenitor population along with Shh, Ptch1, Smo and Gli1 expression in aplasia group. This investigation suggests that pesticide-induced downregulation of two critically important proteins--Ptch1 and Gli1--inside the haematopoietic stem and progenitor cell population impairs haematopoietic homeostasis and regeneration mechanism in vivo concurrent with bone marrow aplasia.
authors.affiliation: Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, Kolkata, India.
authors.forename: Malay
authors.initials: M
authors.lastname: Chaklader
authors.forename: Prosun
authors.initials: P
authors.lastname: Das
authors.forename: Jacintha Archana
authors.initials: JA
authors.lastname: Pereira
authors.forename: Samaresh
authors.initials: S
authors.lastname: Chaudhuri
authors.forename: Sujata
authors.initials: S
authors.lastname: Law
mesh_terms: D000818:Animals; D001855:Bone Marrow Diseases / Q000139:chemically induced* / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics*; D007306:Insecticides / Q000633:toxicity*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D051379:Mice; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D000071676:Zinc Finger Protein GLI1
chemical_list: C498521:Gli1 protein, rat; D053823:Hedgehog Proteins; D007306:Insecticides; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; C000606239:Ptch1 protein, rat; D011956:Receptors, Cell Surface; C546888:Shh protein, rat; D000071676:Zinc Finger Protein GLI1