TCDD Traps Long-Term Hematopoietic Stem Cells and Skews Myeloid Commitment in Ex Vivo Mouse Bone Marrow

This study hypothesized that TCDD exposure disrupts hematopoiesis by perturbing the maintenance and differentiation of hematopoietic stem and progenitor cells (HSPCs). Bone marrow from adult male mice was used to isolate HSPCs, which were expanded in culture and then exposed to TCDD (0.1, 1, and 10 nM). Cell maintenance and differentiation were analyzed using multiparameter flow cytometry, transcriptomic analysis, real-time PCR, cytokine assays, and colony-forming unit (CFU) assays. TCDD treatment significantly enriched the long-term hematopoietic stem cell (LT-HSC) populations, accompanied by upregulation of mRNA expression of self-renewal regulators, including Sca-1, Runx-1, Gata-2, Gata-3 , and c-Kit . The development of multipotent progenitors (MPPs), common myeloid progenitors (CMPs), and granulocyte-monocyte progenitors (GMPs) was significantly reduced, and significantly lower Cebpα levels, a master transcription factor for myeloid differentiation, revealed a differentiation bottleneck. Even with stable megakaryocyte-erythroid progenitor (MEP) numbers, functional output to CFU-E (and mature erythrocytes) was found to be significantly reduced in all TCDD groups, and was supported by transcriptome down-regulation of beta-globin genes ( Hbb-bs, Hbb-bt ) and erythroid-regulated genes ( Klf-1, EpoR ). Similarly, the common lymphoid progenitors (CLPs) remained unchanged; TCDD compromised their B-lymphoid differentiation potential, as revealed by the CFU-preB assay. The data collectively show that TCDD inhibits LT-HSC differentiation and lineage commitment in a dose-dependent manner, shifting the population toward a myeloid-biased state and impairing functional output, with reduced erythroid and B-lymphoid lineages. This connection suggests that environmental exposure to TCDD could lead to long-term health issues, such as immunodeficiency and anemia. SYNOPSIS: TCDD perturbs bone marrow hematopoiesis.