![]() Disruption of these molecular pathways leads to anemia and myeloproliferative syndromes. ![]() At a molecular level, activation of GATA-1, STAT-5, and Kruppel-like factor-1 (KLF-1) pathways ensures that erythroid differentiation and maturation take place. ![]() During erythropoiesis, MEP differentiates into burst-forming unit erythroid (BFU-E) and, finally, into colony-forming unit erythroid (CFU-E) this whole process is tightly modulated by soluble mediators such as erythropoietin (EPO), stem cell factor (SCF), and IL-3 and -6. MEP, under erythropoietin modulation (EPO), initiates erythropoiesis originating erythrocytes and, under thrombopoietin (TPO) effects, MEP originates megakaryocytes and platelets. GMP differentiation is dependent on secretion of granulocyte-macrophage-colony-stimulating factor (GM-CSF), after which macrophage-colony-stimulating factor (M-CSF) modulates the differentiation of monocytes/macrophages and granulocyte-colony-stimulating factor (G-CSF) modulates the differentiation of neutrophils, basophils, and eosinophils the latter in a process known as granulopoiesis. On the other hand, MPP fate-decision differentiation into CMP, which originates granulocyte-macrophage (GMP) and megakaryocyte-erythrocyte progenitors (MEPs), is modulated by PU.1 and GATA-1. Soluble factors such as IL-7 and its receptor (CD127) actively participate in CLP maturation and development, as IL-7 and CD127 deficiencies disrupt production of B and T cells. MPPs differentiated into CLPs originate lymphocytes and natural killer cells that rely mainly on activation of PU.1, Ikaros and GATA-3 transcription factors. MPPs give rise to common myeloid precursors (CMPs) and lymphoid precursors (CLPs) through cytokine signaling and the activation of several transcription factors. These cells remain mostly quiescent at the G0 phase of the cell cycle, but through signaling mediated by intrinsic and extrinsic factors, this population initiates cell cycle entry and starts differentiating. These cells have limited self-renewal capabilities, yet possess full-lineage differentiation potential. In bone marrow (BM), HSCs initially give rise to multipotent progenitors (MPPs), which can also be considered pluripotent. This review aims to describe the most recently investigated molecular and cellular toxicity mechanisms of current major environmental pollutants on hematopoiesis in the bone marrow. Environmental and occupational pollutants, therapeutic molecules, drugs of abuse, and even nutritional status can directly affect progenitor cells at their differentiation and maturation stages, altering behavior and function of blood compounds and resulting in impaired immune responses, anemias, leukemias, and blood coagulation disturbances. The constant high production and delivery of cells into the bloodstream, alongside the fact that blood cells can also circulate between tissues, makes the hematopoietic system a prime target for toxic agents to act upon, making the understanding of the bone marrow microenvironment vital for both toxicological sciences and risk assessment. Senescent leukocytes, specially granulocytes, return to the bone marrow to be phagocytized by macrophages, restarting granulopoiesis. Leukocytes circulate and reach different tissues, returning or not returning to the bloodstream. ![]() Bone marrow platelets, mature erythrocytes and leukocytes are delivered into the bloodstream readily available to meet body demands. A myriad of cell subtypes can be found in the bone marrow at different levels of activation, being also under constant action of an extensive amount of diverse chemical mediators and enzymatic systems. Hematopoiesis in adults takes place in the bone marrow, which is endowed with an extensive vasculature conferring an intense flow of cells. These cells can originate other cell subtypes that are responsible for maintaining vital functions, mediate innate and adaptive immune responses, provide tissues with oxygen, and control coagulation. It is orchestrated mostly by hematopoietic progenitor cells (hematopoietic stem cells (HSCs)) that are capable of self-renewal and differentiation. Hematopoiesis is a complex and intricate process that aims to replenish blood components in a constant fashion.
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