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Exposure to high-dose benzene leads to the inhibition of erythroid differentiation. However, whether lower doses of benzene exposure resemble high-dose effects in erythroid differentiation, as well as the underlying mechanisms, remains largely unknown. To identify the microRNAs (miRNAs) specifically responsible for benzene exposure and their regulatory role in erythroid differentiation, we performed miRNA microarray in CD34 hematopoietic progenitor cells isolated from human umbilical cord blood after treatment with hydroquinone (HQ), a metabolite of benzene at concentrations of 0, 1.0, 2.5, and 5.0 μM. As a result, HQ treatment inhibited erythroid differentiation in a dose-response manner. miRNA microarray analysis revealed that miRNA-451a, miRNA-486-5p and miRNA-126-3p expression were significantly lower in HQ-treated CD34 hematopoietic progenitor cells. In vitro studies showed that miRNA-451a and miRNA-486-5p were up-regulated during erythroid differentiation both in CD34 hematopoietic progenitor cells and K562 cells. The increase in the percentage of benzidine-positive cells and the expression of γ-globin in K562 cells transfected with either miRNA-451a or miRNA-486-5p mimic indicated that both miRNAs played a role in the promotion of erythroid cell differentiation. Overexpression of either miRNA-451a or miRNA-486-5p attenuated the inhibitory effects on erythroid differentiation in HQ-treated K562 cells. In vivo study showed a decreasing count of peripheral red blood cell (RBC) in C57BL/6J male mice treated with aerosol benzene at concentrations of 0, 1, 5, 25 ppm (time weight average, TWA). In addition, the expression of miRNA-451a or miRNA-486-5p was negatively correlated with the concentration of benzene inhalation on erythroid toxicity of C57BL/6J mice. Particularly, the decline in miRNA-451a and miRNA-486-5p expression appeared in male chronic benzene poisoning patients, and was correlated with a constant decrease in their RBC counts over the first 3 months after being diagnosed. These findings indicate that the suppression of miRNA-451a or miRNA-486-5p might be associated with the benzene-induced perturbation of erythroid cell differentiation. [ABSTRACT FROM AUTHOR]

The MiR-146a/TRAF6/NF-κB axis is important for the regulation of hematopoiesis and the immune system. To identify the key axis that regulates benzene-induced hematotoxicity or even leukemia, we investigated miR-146a expression in human CD34+ hematopoietic progenitor cells (HPCs) and human acute promyelocytic leukemia cells (HL-60) during the differentiation process. By performing a colony formation assay and flow cytometry on cells in the differentiation process after hydroquinone treatment, we found that hydroquinone induced a marked reduction of differentiation toward myeloid cells and immune cells in CD34+ cells (5 days exposure) as well as in HL-60 cells (3 h exposure). Further study using real-time PCR and western blot showed that the impaired myeloid differentiation was accompanied by the up-regulation of miR-146a and the down-regulation of TRAF6 and NF-κB. Using the miR-146a-5p inhibitor to suppress miR-146a expression could relieve the inhibitory effect on myeloid differentiation induced by hydroquinone to a certain extent. At the same time, the level of TRAF6 protein, as well as the phosphorylated IκBα protein which indicates NF-κB transcriptional activity was restored to the same levels as the control group. These results suggested that hydroquinone induced a dysregulation of miR-146a and its downstream NF-κB transcriptional factor pathway, which might be an early event in the generation of benzene-induced differentiation disturbance and subsequent leukemogenesis. [ABSTRACT FROM AUTHOR]

Objective: To illustrate the significance of combined detection of anti cardiolipin (ACL) and anti-β2-glycoprotein 1 (β2-GP1) in the diagnosis of adverse pregnancy., Methods: 60 postnatal women with adverse pregnancy presented to our hospital from March 2019 to March 2020 were enrolled as the experimental group, and 60 postnatal women with normal delivery in the same period were selected as the control group. The levels of ACL, β2-GP1 were measured to analyze the significance of the integrated detection in the diagnosis of adverse pregnancy., Results: No obvious differences were observed in mean age, mean gestational week, mean height, number of cases of primigravida and multiparous women, educational background, place of residence between two groups ( P > 0.05). The number of cases of positive β2-GP1-IgG and β2-GP1-IgM tests in experimental group were remarkably higher ( P < 0.05). The number of β2-GP1-IgA positive cases in the two kinds of parturients was not notably different ( P > 0.05). The ACL of the experimental parturients had a notably higher number of β2-GP1-positive cases ( P < 0.001), and the combined positive cases of the experimental parturients had notably higher serum BPA and resistin levels ( P < 0.001). The incidence of fetal growth restriction, premature delivery and placental abruption of experimental group were higher than those of control group (P < 0.05). There was no stillbirth in both groups., Conclusions: The positive expression of ACL with β2-GP1 is the culprit of adverse pregnancy, and the combined diagnosis can greatly improve the clinical screening rate of adverse pregnancy and provide more evidence for subsequent treatment., Competing Interests: None., (AJTR Copyright © 2021.)

The MiR-146a/TRAF6/NF-κB axis is important for the regulation of hematopoiesis and the immune system. To identify the key axis that regulates benzene-induced hematotoxicity or even leukemia, we investigated miR-146a expression in human CD34 + hematopoietic progenitor cells (HPCs) and human acute promyelocytic leukemia cells (HL-60) during the differentiation process. By performing a colony formation assay and flow cytometry on cells in the differentiation process after hydroquinone treatment, we found that hydroquinone induced a marked reduction of differentiation toward myeloid cells and immune cells in CD34 + cells (5 days exposure) as well as in HL-60 cells (3 h exposure). Further study using real-time PCR and western blot showed that the impaired myeloid differentiation was accompanied by the up-regulation of miR-146a and the down-regulation of TRAF6 and NF-κB. Using the miR-146a-5p inhibitor to suppress miR-146a expression could relieve the inhibitory effect on myeloid differentiation induced by hydroquinone to a certain extent. At the same time, the level of TRAF6 protein, as well as the phosphorylated IκBα protein which indicates NF-κB transcriptional activity was restored to the same levels as the control group. These results suggested that hydroquinone induced a dysregulation of miR-146a and its downstream NF-κB transcriptional factor pathway, which might be an early event in the generation of benzene-induced differentiation disturbance and subsequent leukemogenesis.