Regulation of in vitro human hematopoietic differentiation by dioxin-like compounds

Abstract

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 the presence of TCDD and DLCs at concentrations ranging from 0.1 to 50 nM. Cells were collected every 7 days for analysis. TCDD, PeCDF, PCB-126, 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.