Nitrogen Dioxide Inhalation Disrupts Bone Marrow Hematopoiesis by Inducing Stage-Specific Developmental Blockage in Erythroid and Granulocytic Lineages in Mice.

Nitrogen dioxide (NO2) exposure is a known risk factor for respiratory, cardiovascular, and neurological diseases and has also been linked to systemic hematological alterations, including an increased risk of anemia. However, the effects of NO2 exposure on the immune and hematopoietic function, which play a crucial role in the pathogenesis of these disorders, remain unclear. In this study, mice were exposed to environmentally relevant concentrations of NO2 (2.5 ppm, 5 h/day) for 28 days to investigate systemic immune and hematopoietic effects across the lung, spleen, and bone marrow (BM). NO2 exposure triggered experimental anemia, with approximately 10% decreases in red blood cell (RBC) count and hemoglobin (HGB) concentration. Further investigation revealed a heightened sensitivity of the BM to NO2 exposure. Notably, NO2-induced hematopoietic and immune dysregulation was specific to the BM, with minimal effects observed in the peripheral lung or spleen. Flow cytometry analysis indicated disrupted erythropoiesis, characterized by an expansion of precolony-forming unit-erythroid (preCFU-E) precursors and a differentiation block at the orthochromatic erythroblast (ortho-EB) stage. Granulopoiesis in the BM was also altered, with a 31% decrease in mature neutrophils (NEs), potentially due to developmental defects at the metamyelocyte (MM) stage. In addition, upstream hematopoietic progenitors, including common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs), were significantly expanded, potentially reflecting myeloid-lineage compensation for RBC and NE deficits and broader hematopoietic stress. This study reveals that NO2 exposure can lead to both erythroid and granulocytic hematopoietic abnormalities in the BM, providing novel mechanistic insights into the potential health risks associated with NO2.