Certain dioxin-like-compounds (DLCs) pose health concerns. However, their impact on human hematopoiesis has not been explored. Role of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 3,4,4',5-tetrachlorobiphenyl (PCB81), and 3,3',4,4',5-pentachlorobiphenyl (PCB126) in lineage specification from human cord-blood derived CD34⁺ hematopoietic stem and progenitor cells (HSPCs) was investigated. We compared these DLCs in relation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Over a 28-day period, HSPCs were cultured in vitro in presence of TCDD and DLCs at concentrations ranging from 0.1 to 50nM. Cells were collected every 7 days for analysis. TCDD, PeCDF, and PCB-81 reduced percentage of CD10⁺ lymphoid progenitors and CD10 protein expression in a concentration-dependent manner. PeCDF was more potent than TCDD, and PCB81 had higher potency than PCB126. TCDD and PeCDF also induced reduction in CD34 expressing cells and CD1c⁺ dendritic cells, and an increase in promyelocytes at multiple time-points. These changes were mediated through the aryl hydrocarbon receptor (AHR). With increasing concentrations of TCDD and PeCDF, there was a trend towards decreases in CD41⁺ megakaryocyte progenitors and increases in CD14⁺ monocytes. This study demonstrated that these DLCs altered human HSPC differentiation process towards specific myeloid hematopoietic lineages at the expense of lymphoid progenitors, similar to TCDD, which may lead to reduced immune competence. Lineages that were most sensitive to developmental modulation by DLCs were identified. Interestingly, the relative potency of these DLCs in eliciting these effects in humans was different from the compounds' relative toxicological profiles as reported in murine studies, with important implications for human risk assessment for these compounds.

Keywords: Dioxins; Hematopoiesis; Risk assessment; aryl hydrocarbon receptor; immunotoxicity; in vitro.

Copyright © 2025. Published by Elsevier B.V.

某些具有二噁英类似物（DLCs）的化合物对健康存在担忧。然而，它们对人体造血系统的影响尚未被研究过。本文调查了2,3,4,7,8-五氯二苯并呋喃 (PeCDF)、3,4,4′,5-四氯联苯 (PCB81) 和 3,3′,4,4′,5-五氯联苯 (PCB126) 在从脐带血衍生的 CD34+ 造血干细胞和祖细胞（HSPCs）谱系特化中的作用。我们将这些 DLCs 与 2,3,7,8-四氯二苯并二恶烷（TCDD）进行了比较。在为期28天的时间里，HSPCs 在含有 TCDD 和 DLCs 的浓度范围为0.1到50nM的体外培养中进行培养。每隔7天收集细胞进行分析。TCDD、PeCDF 和 PCB-81 以剂量依赖的方式降低了 CD10+ 淋巴系祖细胞和CD10蛋白表达水平。PeCDF 的效力比 TCDD 更强，而PCB81的效力则高于PCB126。TCDD 和 PeCDF 还在多个时间点诱导了CD34阳性细胞和CD1c+ 树突状细胞减少以及原始髓系细胞增多的现象。这些变化是通过芳烃受体（AHR）介导的。随着 TCDD 和 PeCDF 浓度的增加，CD41+ 髓样祖细胞的数量趋于下降，而 CD14+ 单核细胞数量则趋于上升。该研究展示了这些 DLCs 使人类 HSPC 分化过程倾向于特定髓系造血谱系的发展，从而以牺牲淋巴系祖细胞为代价，类似于 TCDD 的影响，这可能导致免疫功能减弱。确定了对DLCs 发展调节最敏感的谱系。值得注意的是，在人体内，这些DLCs 产生上述效应的相对效力与小鼠研究中报告的有毒理学特征不同，这对这些化合物的人类风险评估具有重要意义。

关键词：二噁英；造血系统；风险评估；芳烃受体；免疫毒性；体外实验。