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. Arh Hig Rada Toksikol 2012;63:271-282 A surge of numerous organophosphates, pyrethroids (analogs of naturally occurring phytopyrethrins), and thiazole fungicides replaced DDT after the ban in 1993. Depending on the physiological activity, synthetic pyrethroids are of two distinct types: Type I pyrethroids, which do not contain the α-cyano group, and Type II pyrethroids, which have the α-cyano group (1-3). Previous studies have affi rmed the genotoxic and/or cytotoxic effects of Type II pyrethroids such as cyfl uthrin, cypermethrin etc. (4-9). The carcinogenic potential of pyrethroids was also reported on the murine model (9). A few recent studies revealed that besides blocking neurotransmission, both pyrethroids and organophosphate pesticides can cause Unauthenticated Download Date | 5/12/18 12:23 AM
KEY WORDS: bone marrow suppression, haematopoietic stem cell, patched, smoothened, sonic hedgehog Chaklader M, et al. ALTERED HH-GLI SIGNALLING IN PESTICIDE-INDUCED BONE MARROW APLASIA