Morphogen signaling by Wnt/β-catenin pathway and microenvironmental alteration in the bone marrow of agricultural pesticide exposure-induced experimental aplastic anemia

The etiologic link between pesticide toxicity and aplastic anemia in agricultural and agro-industrial setting has been frequently reported in epidemiological studies conducted worldwide. Chronic pesticide toxicity causes long-term bone marrow injury and perturbs the normal hematopoietic physiology, including survival of hematopoietic progenitor cells and bone marrow's blood cell forming ability. The purpose of this study is to understand the mechanism of pesticide toxicity-mediated bone marrow aplasia by studying Wnt/beta-catenin signaling pathway and microenvironmental stromal components. An agricultural pesticide formulation comprising of cypermethrin, chlorpyriphos, and hexaconazole was used to induce bone marrow aplasia in inbred Swiss albino mice. Marrow failure followed by the onset of aplastic condition was confirmed by pancytopenic peripheral blood and hypocellular bone marrow filled with adipocytes. Significant downregulation of canonical Wnt/beta-catenin signaling was identified by expression analysis of Wnt3a, beta-catenin, and telomerase reverse transcriptase in the aplastic bone marrow hematopoietic stem/progenitor compartment. Along with signaling deregulation, disruption in both the osteoblastic and vascular stromal components was observed in the pesticide-exposed bone marrow microenvironment when compared to control. In this study, we tried to establish the correlation among disease pathophysiology, signaling deregulation in the hematopoietic cells, and bone marrow microenvironmental alteration during environmental exposure-mediated aplastic hematopoietic catastrophe, which may shed light on the unexplored mechanistic perspective of this fatal blood disease.