<jats:bold>Background: </jats:bold>Di(2-ethylhexyl)phthalate (DEHP) is one of the phthalates most widely used to manufacture various plastic products. However, the potential effects of DEHP on erythropoiesis have not been investigated comprehensively. Here, we aimed to investigate whether DEHP modulate the function of haematopoietic stem and progenitor cell (HSPC) to influence erythropoiesis, and to explore the associated mechanism.<jats:bold>Results: </jats:bold>In the present study, human cell lines with a capacity to differentiate into erythroid cells and murine bone marrow cells were treated with DEHP. DEHP not only impaired HSPC function but also suppressed erythroid differentiation in a dose-dependent manner. In addition, DEHP removal restored HSPC activity. To explore how DEHP interferes with erythroid differentiation, we focused on energy metabolism and <jats:italic>Klotho</jats:italic> expression. DEHP suppressed erythroid differentiation via upregulation of<jats:italic> Klotho </jats:italic>expression in erythroblasts and not via cellular bioenergetic modulation.<jats:bold>Conclusion: </jats:bold>Here, we have demonstrated a novel pathophysiological role of DEHP in erythroid differentiation. DEHP impaired erythroid differentiation by inducing <jats:italic>Klotho</jats:italic> expression and not by reprogramming cellular bioenergetic profiles during differentiation.
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