Ethanol exhibits specificity in its effects on differentiation of hematopoietic progenitors

Abstract

Ethanol is a known teratogen but the mechanisms by which this simple compound affects fetal development remain unresolved. The goal of the current study was to determine the mechanism by which ethanol affects lymphoid differentiation using an in vitro model of ethanol exposure. Primitive hematopoietic oligoclonal neonatal progenitor cells (ONP), with the phenotype Lin − HSA lo CD43 lo Sca-1 − c-Kit + that are present in neonatal but not adult bone marrow were sorted from the bone marrow of 2-week-old C57BL/6J mice and cultured under conditions that favor either B cell or myeloid cell differentiation with or without addition of ethanol. The overall growth of the ONP cells was not significantly affected by inclusion of up to 100mM ethanol in the culture medium. However, the differentiation of the progenitor cells along the B-cell pathway was significantly impaired by ethanol in a dose dependent manner. Exposure of ONP cells to 100mM ethanol resulted in greater than 95% inhibition of B cell differentiation. Conversely, ethanol concentrations up to and including 100mM had no significant effect on differentiation along the myeloid pathway. The effect of ethanol on transcription factor expression was consistent with the effects on differentiation. ONP cells grown in 100mM ethanol failed to up-regulate Pax5 and EBF, transcriptional regulators that are necessary for B cell development. However, ethanol had no significant effect on the up-regulation of PU.1, a transcription factor that, when expressed in high concentration, favors myeloid cell development. Taken together, these results suggest that ethanol has specificity in its effects on differentiation of hematopoietic progenitors.

Determination of Genotype Combinations That Can Predict the Outcome of the Treatment of Alcohol Dependence Using the 5-HT3 Antagonist Ondansetron

“…However, given their location within the genes, it is possible that all three of these polymorphisms may alter mRNA expression levels. The rs1150226 is located in the promoter region of HTR3A within 1 kb of putative binding sites for several transcription factors that have been shown to be modulated by ethanol (41, 42). Furthermore, genetic association analyses have shown an association of rs1150226 with alcoholism comorbid with antisocial personality disorder (16), altered temporal lobe activity (43), and clozapine treatment outcome for schizophrenia (44).…”

Dysregulation of Myelopoiesis by Chronic Alcohol Administration During Early SIV Infection of Rhesus Macaques

“…Our examination of CLPs showed a robust increase in the frequency of these progenitors in the alcohol-administered animals after 3 months. Studies in mice have demonstrated that in vitro alcohol can inhibit B cell differentiation at the stage of the CLP (Wang et al, 2009). Our results suggest that the CLP differentiation is inhibited by alcohol administration, leading to an accumulation of this progenitor.…”

Alcohol Affects the Late Differentiation of Progenitor B Cells

“…Previous studies showed that alcohol can affect the ONP cell differentiation into a B lineage both in vitro and in vivo (Wang et al, 2006(Wang et al, , 2009. However, it is important to know; (a) whether alcohol affects cell differentiation at an early stage, late stage or on both stages, (b) does the effect of alcohol on B-cell differentiation temporary or permanent and (c) the mechanism by which alcohol affects the progenitor B-cell differentiation.…”

“…TFs activate or repress target genes and signaling receptors induce or modify the activities of gene regulatory proteins. Previous studies in this laboratory showed that ONP cells sorted from alcohol-exposed animals failed to up-regulate IL-7Rα and had decreased expression levels of down-stream EBF and Pax5 during in vitro culture under conditions that favored differentiation to the B lineage (Wang et al, 2009). This indicated the impaired commitment of progenitors to the B lineage.…”