Abstract
Anemia is a hematological disorder that adversely affects the health of millions of people worldwide. Although many variables influence the development and exacerbation of anemia, one major contributing factor is the impairment of erythropoiesis. Normal erythropoiesis is highly regulated by the zinc finger transcription factor GATA-1. Disruption of the zinc finger motifs in GATA-1, such as produced by germline mutations, compromises the function of this critical transcription factor and causes dyserythropoietic anemia. Herein, we utilize a combination of in vitro and in vivo studies to provide evidence that arsenic, a widespread environmental toxicant, inhibits erythropoiesis likely through replacing zinc within the zinc fingers of the critical transcription factor GATA-1. We found that arsenic interacts with the N- and C-terminal zinc finger motifs of GATA-1, causing zinc loss and inhibition of DNA and protein binding activities, leading to dyserythropoiesis and an imbalance of hematopoietic differentiation. For the first time, we show that exposures to a prevalent environmental contaminant compromises the function of a key regulatory factor in erythropoiesis, producing effects functionally similar to inherited GATA-1 mutations. These findings highlight a novel molecular mechanism by which arsenic exposure may cause anemia and provide critical insights into potential prevention and intervention for arsenic-related anemias.
Highlights
Anemia is a hematological disorder that adversely affects the health of millions of people worldwide
Erythropoiesis is a dynamic and precisely regulated process under the control of many regulatory factors[14,15,16], among which GATA-1 is recognized as the master regulatory factor and its activity is necessary for the normal differentiation of early erythroid progenitors (i.e. burst-forming unit erythroid cells (BFU-E), CFU-E, and proerythroblasts)[15,17,18]
As an effort to characterize the inhibitory effects of AsIII on erythropoiesis and to investigate whether AsIII impairs other hematopoietic lineages, we developed an in vitro model of erythropoiesis using primary mouse bone marrow hematopoietic progenitor cells (HPC) stimulated with erythropoietin (EPO) and stem cell factor (SCF)[51]
Summary
Anemia is a hematological disorder that adversely affects the health of millions of people worldwide. Disruption of the zinc finger motifs in GATA-1, such as produced by germline mutations, compromises the function of this critical transcription factor and causes dyserythropoietic anemia. We show that exposures to a prevalent environmental contaminant compromises the function of a key regulatory factor in erythropoiesis, producing effects functionally similar to inherited GATA-1 mutations These findings highlight a novel molecular mechanism by which arsenic exposure may cause anemia and provide critical insights into potential prevention and intervention for arsenic-related anemias. Erythropoiesis is a dynamic and precisely regulated process under the control of many regulatory factors[14,15,16], among which GATA-1 is recognized as the master regulatory factor and its activity is necessary for the normal differentiation of early erythroid progenitors (i.e. BFU-E, CFU-E, and proerythroblasts)[15,17,18]. PU. binds to purine-rich DNA consensus sequences (GAGGAA), and is responsible for activating the expression of genes required for myelopoiesis and cellular communications of the immune s ystem[12,13,30]
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