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Archives of Industrial Hygiene and Toxicology

The Journal of Institute for Medical Research and Occupational Health

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Volume 63, Issue 3


Altered canonical hedgehog-gli signalling axis in pesticide-induced bone marrow aplasia mouse model

Malay Chaklader
  • Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, Kolkata, India
  • Other articles by this author:
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/ Prosun Das
  • Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, Kolkata, India
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jacintha Archana Pereira
  • Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, Kolkata, India
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  • De Gruyter OnlineGoogle Scholar
/ Samaresh Chaudhuri / Sujata Law
  • Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, Kolkata, India
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2012-09-25 | DOI: https://doi.org/10.2478/10004-1254-63-2012-2255

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 confi rmed 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.

KEYWORDS: : bone marrow suppression; haematopoietic stem cell; patched; smoothened; sonichedgehog

  • 1. Elliot T. Established pyrethroid insecticides. Pestic Sci 1980;11:119-28.CrossrefGoogle Scholar

  • 2. Tabarean IV, Narahashi T. Potent modulation of tetradotoxinsensitive and tetradotoxin-resistant sodium channels by the type II pyrethroid deltamethrin. J Pharmacol Exp Ther 1998;284:958-65.Google Scholar

  • 3. Chandra S, Saxena PN, Gupta SK. In vivo cytogenetic effects of a commercially formulated mixture of cypermethrin and quinalphos in mice. Mutat Res 2005;587:120-5.Google Scholar

  • 4. Chauhan LK, Kumar M, Paul BN, Goel SK, Gupta SK. Cytogenetic effects of commercial formulations of deltamethrin and/or isoproturon on human peripheral lymphocytes and mouse bone marrow cells. Environ Mol Mutagen 2007;48:636-43.CrossrefPubMedGoogle Scholar

  • 5. Celik A, Mazmancı B, Camlıca Y, Comelekoğlu Y, Askın A. Evaluation of cytogenetic effects of k-cyhalothrin in wistar rat bone marrow by gavage administration. Ecotoxicol Environ Saf 2005;61:128-33.CrossrefGoogle Scholar

  • 6. Celik A, Mazmancı B, Camlıca Y, Askın A, Comelekoğlu U. Induction of micronuclei by k-cyhalothrin in wistar rat bone marrow and gut epithelial cells. Mutagenesis 2005;20:125-9.CrossrefGoogle Scholar

  • 7. Giri A, Giri S, Sharma GD. Malathion and fenvalerate induce micronuclei in mouse bone marrow cells. Environ Mol Mutagen 2011;52:607-13.PubMedCrossrefGoogle Scholar

  • 8. Jamil K, Shaik AP, Mahboob M, Krishna D. Effect of organophosphorus and organochlorine pesticides (monocrotophos, chloropyriphos, dimethoate and endosulfan) on human lymphocyte cultures 2004;27:133-44.Google Scholar

  • 9. Shukla Y, Yadav A, Arora A. Carcinogenic and cocarcinogenic potential of cypermethrin on mouse skin. Cancer Lett 2002;182:33-41.CrossrefPubMedGoogle Scholar

  • 10. Litchfi eld MH. Toxicity to mammals. In: Leahey JP, editors. The pyrethroid insecticides. London: Taylor & Francis; 1985. p. 99-149.Google Scholar

  • 11. Broughton A, Thrasher JD, Madison R. Chronic health effects and immunological alterations associated with exposure to pesticides. Comments Toxicol 1990;4:59-71.Google Scholar

  • 12. Holladay SD, Luster MI. Alterations in fetal thymic and liver hematopoietic cells as indicators of exposure to developmental immunotoxicants. Environ Health Perspect 1996;104(Suppl 4):809-13.PubMedGoogle Scholar

  • 13. Repetto R, Baliga SS. Pesticide and immunosuppression: the risks to public health. Health Policy Plan 1997;12:97-106.PubMedCrossrefGoogle Scholar

  • 14. Kevin Y, Urayama JK, Wiencke B, Chokkalingam AP, Metayer C, Wiemels JL. MDR1 Gene variants, indoor insecticide exposure, and the risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev 2007;16:1172-7.Google Scholar

  • 15. Ledirac N, Antherieu S, Uby AD, Caron JC, Rahmani R. Effects of organochlorine insecticides on MAP kinase pathways in human HaCaT keratinocytes: key role of reactive oxygen species. Toxicol Sci 2005;86:444-52.PubMedCrossrefGoogle Scholar

  • 16. Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, Reya T, Liu JO, Epstein EH, David A. Stevens DA, Beachy PA. Itraconazole, a commonly used antifungal that inhibits hedgehog pathway activity and cancer growth. Cancer Cell 2010;17:388-99.CrossrefPubMedGoogle Scholar

  • 17. Laryea D, Gullbo J, Isaksoon A, Larsson R, Nygren P. Characterization of the cytotoxic properties of the benzimidazole fungicide, benomyl and carbendazim, in human tumor cell lines and primary culture of patient tumor cells. Anticancer Drugs 2010;21:33-42CrossrefPubMedGoogle Scholar

  • 18. Young NS, Issaragrisil S, Ch’en WC, Takaku F. Aplastic anemia in the Orient. Br J Haematol 1986;62:1-6.CrossrefGoogle Scholar

  • 19. Muir KR, Chilvers CED, Harriss C, Coulson L, Grainge M, Darbyshire P, Geary CJ, Hows J, Marsh T, Rutherford M, Taylor E, Gordon-Smith EC. The role of occupational and environmental exposures in the aetiology of acquired severe aplastic anaemia: a case control investigation. Br J Haematol 2003;123:906-14.PubMedCrossrefGoogle Scholar

  • 20. Fleming LE, Timmeny W. Aplastic anemia and pesticides. An etiologic association? J Occup Med 1993;35:1106-16.PubMedCrossrefGoogle Scholar

  • 21. Botnick LE, Hannon EC, Hellman S. A long lasting proliferative defect in the hematopoietic stem cell compartment following cytotoxic agents. Int J Radiat Oncol Biol Phys 1979;5:1621-5.PubMedCrossrefGoogle Scholar

  • 22. Prihartono N, Kriebel D, Woskie S, Thetkhathuek A, Sripaung N, Padungtod C, Kaufman D. Risk of aplastic anemia and pesticide and other chemical exposures. Asia Pac J Public Health 2011;23:369-77.PubMedCrossrefGoogle Scholar

  • 23. Rugman FP, Cosstic R. Aplastic anemia associated with organochlorine pesticides: Case reports and review of evidence. J Clin Pathol 1990;43:98-101.CrossrefPubMedGoogle Scholar

  • 24. Sanchez-Medal L, Castando JP, Garcia-Rojas F. Insecticides and aplastic anemia. N Engl J Med 1963;269:1365-7.Google Scholar

  • 25. Wang HH, Grufferman S. Aplastic anemia and occupational pesticide exposure: a case control study. J Occup Med 1981;23:364-6.PubMedGoogle Scholar

  • 26. Rau ATK, Coutinho A, Avabratha KS, Rau AR, Warrier RP. Pesticide (endosulfan) levels in the bone marrow of children with hematological malignancies. Indian Pediatr 2012;49:113-7.PubMedCrossrefGoogle Scholar

  • 27. Chatterjee S, Basak P ,Chaklader M, Das P, Pereira JA, Chaudhuri S, Law S. Pesticide induced marrow toxicity and effects on marrow cell population and on hematopoietic stroma. Exp Toxicol Pathol 2011 Oct 15. [Epub ahead of print]Google Scholar

  • 28. Chatterjee S, Chaklader M, Basak P, Das P, Das M, Pereira JA, Dutta RK, Chaudhuri S, Law S. An animal model of chronic aplastic bone marrow failure following pesticide exposure in mice. Int J Stem Cells 2010;3:54-62.Google Scholar

  • 29. Law S, Basu K, Banerjee S, Begum B, Chaudhuri S. Cord blood derived plasma factor (CBPF) potentiated the low cytokinetic and immunokinetic profi le of bone marrow cells in pesticide victims suffering from Acquired Aplastic Anaemia (AAA): an 2006;35:209-25.Google Scholar

  • 30. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980;287:795-801.Google Scholar

  • 31. Roy S, Ingham PW. Hedgehogs tryst with the cell cycle. J Cell Sci 2002;115:4393-97.CrossrefPubMedGoogle Scholar

  • 32. Kalderon D. Transducing the hedgehog signal. Cell 2000;103:371-4.PubMedCrossrefGoogle Scholar

  • 33. Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of Smoothened. Nature 2002;418:892-7.Google Scholar

  • 34. Adolphe C, Hetherington R, Ellis T, Wainwright B. Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res 2006;66:2081-8.PubMedGoogle Scholar

  • 35. Lee J, Platt KA, Censullo P, Ruiz I, Altaba A. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 1997;124:2537-52.PubMedGoogle Scholar

  • 36. Medvinsky A, Dzierzak E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 1996;86:897-906.PubMedCrossrefGoogle Scholar

  • 37. Farrington SM, Belaoussoff M, Baron MH. Winged-helix, Hedgehog and Bmp genes are differentially expressed in distinct cell layers of the murine yolk sac. Mech Dev 1997;62:197-211.CrossrefPubMedGoogle Scholar

  • 38. Dyer MA, Farrington SM, Mohn D, Munday JR, Baron MH. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development 2001;128:1717-30.PubMedGoogle Scholar

  • 39. Cridland SO, Keys JR, Papathanasiou P, Perkins AC. Indian hedgehog supports defi nitive erythropoiesis. Blood Cells Mol Dis 2009;43:149-55.CrossrefGoogle Scholar

  • 40. Hofmann I, Stover EH, Cullen DE, Mao J, Morgan KJ, Lee BH, Kharas MG, Miller PG, Cornejo MG, Okabe R, Armstong SA, Ghilardi N, Gould S, Sauvage FJ, McMahon AP, Gilliland DG. Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell 2009;4:559-67.CrossrefPubMedGoogle Scholar

  • 41. Gao J, Graves S,Koch U, Liu S, Jankovic V,Buonamici S, Andaloussi AE, Nimer SD, Kee BL, Taichman R, Radtke F, Aifantis I. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell 2009;4:548-58.PubMedCrossrefGoogle Scholar

  • 42. Merchant AA, Matsui W. Smoothening the controversial role of hedgehog in hematopoiesis. Cell Stem Cell 2009;4:470-1.PubMedCrossrefGoogle Scholar

  • 43. Mar BG, Amakye D, Aifantis I, Buonamici S. The controversial role of the Hedgehog pathway in normal and malignant hematopoiesis. Leukemia 2011;25:1665-73.CrossrefPubMedGoogle Scholar

  • 44. Trowbridge JJ, Scott MP, Bhatia. M. Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration. Proc Natl Acad Sci USA 2006;103:14134-9.CrossrefGoogle Scholar

  • 45. Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, Trussell C, Graeff AS, Landwerlin K, Veelken H, Warmuth M. Expansion of Bcr-Abl-Positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008;14:238-49.CrossrefPubMedGoogle Scholar

  • 46. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, Munchhof M, Van Arsdale T, Beachy PA, Reya T. Hedgehog signaling is essential for maintenance of cancer stem cells in myeloid leukemia. Nature 2009;458:776-9.Google Scholar

  • 47. Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE, Karanu FN, Bhatia M. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immunol 2001;2:172-80.CrossrefGoogle Scholar

  • 48. Detmer K, Thompson AJ, Garner RE, Walker AN, Gaffi eld W, Dannaw H. Hedgehog signaling and cell cycle control in differentiating erythroid progenitors. Blood Cells Mol Dis 2005;34:60-70.CrossrefGoogle Scholar

  • 49. Merchant A, Joseph G, Wang O, Brennan S, Matsui W. Gli1 regulates the proliferation and differentiation of HSCs and myeloid progenitors. Blood 2010;115:2391-6.Google Scholar

  • 50. Sengupta A, Banerjee D, Chandra S, Banerji SK, Ghosh R, Roy R, Banerjee S. Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. Leukemia 2007;21:949-55.PubMedGoogle Scholar

  • 51. Bai L-Y, Chiu C-F, Lin C-W, Hsu N-Y, Lin C-L, Lo W-J, Kao M-C. Differential expression of Sonic hedgehog and Gli1 in hematological malignancies. Leukemia 2008;22:226-8.CrossrefGoogle Scholar

  • 52. Chatterjee S, Basak P, Das M, Das P, Pereira JA, Dutta RK, Chaklader M, Chaudhuri S, Law S. Kinetic impairment of haemopoietic stem cells in experimentally induced leukemia and aplastic anemia: an inverse correlation. J Stem Cells 2009;4:179-89.PubMedGoogle Scholar

  • 53. Queiroz MLS, da Rocha MC, Torello CO, Queiroz JS, Bincoletto C, Morgano MA, Romano MR, Paredes-Gamero EJ, Barbosa CMV, Calgarotto AK. Chlorella vulgaris restores bone marrow cellularity and cytokine production in leadexposed mice. Food Chem Toxicol 2011;49:2934-41.CrossrefGoogle Scholar

  • 54. The Niche. Hematopoiesis, no hedgehog needed [displayed 26 July 2012]. Available at http://blogs.nature.com/theniche/2009/06/hematopoiesis_no_hedgehog_need.htmlGoogle Scholar

About the article

Published Online: 2012-09-25

Published in Print: 2012-09-25

Citation Information: Archives of Industrial Hygiene and Toxicology, Volume 63, Issue 3, Pages 271–282, ISSN (Print) 0004-1254, DOI: https://doi.org/10.2478/10004-1254-63-2012-2255.

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