Arsenic exposure disrupts human hematopoiesis by impairing the generation and function of hematopoietic stem and progenitor cells.

Arsenic is a widespread environmental contaminant with well-documented immunotoxic and developmental effects. However, its impact on the earliest stages of human hematopoietic development remains poorly understood. Using human induced pluripotent stem cells (iPSCs), we examined how sodium arsenite (NaAsO₂) affects the formation of hematopoietic stem and progenitor cells (HSPCs), which are essential for lifelong blood production. Exposure to NaAsO₂ during directed differentiation of iPSCs to HSPCs showed that the formation of pre-HSPCs (CD34⁺CD43⁺CD45⁻) were more sensitive, with significant reduction to 45% of the untreated control at 1 µM. In contrast, the formation of mature-HSPCs (CD34⁺CD43⁺CD45⁺) displayed a biphasic response, with a modest elevation to 113% of control at 0.1 µM, followed by significant reduction to 63% of control at 1 µM. Time‑addition experiments revealed that suppression occurred when NaAsO₂ was present during hematopoietic differentiation or across both mesodermal and hematopoietic phases. In contrast, transient exposure during mesoderm alone did not alter HSPC numbers. Functionally, HSPCs derived from NaAsO₂-treated iPSCs showed reduced blood-forming capacity, with marked decreases in erythroid, granulocyte-macrophage, and multipotent progenitors. Gene expression analysis showed downregulation of critical regulators during embryonic hematopoiesis, including mesodermal regulators (MIXL1, TBXT), hematopoietic markers (SPN, PTPRC), and lineage-specific transcription factors (SPI1). Collectively, these findings demonstrate that arsenic perturbs the formation of HSPCs in a stage‑dependent manner, broadening its toxicological relevance from erythropoiesis to the earliest steps of human blood formation.