Biomedical Sciences ETDs

Publication Date

Spring 3-4-2019

Abstract

Anemia adversely impacts the health of more than a billion people worldwide. A strong association between anemia and arsenic exposure has been reported in epidemiological studies from multiple countries. However, the mechanistic bases for the association between arsenic exposure and anemia is not fully understood. In this study, we found an inverse association between drinking water arsenic exposures and clinical indicators of anemia (i.e., red blood cell counts and hematocrit/packet cell volumes) in a cohort of men from rural Bangladesh enrolled in the Health Effects of Arsenic Longitudinal Study.

Follow-up studies in mice, revealed that 60-day exposure to trivalent inorganic arsenic (arsenite, As+3) via drinking water resulted in anemia due to the impaired development of early erythroid progenitor cells in the bone marrow. To gain an understanding of the mechanisms of As+3-inducedsuppression of erythroid progenitor cell development, we utilized an in vitro model of erythropoiesis using primary mouse bone marrow hematopoietic progenitor cells. As+3 and the As+3 metabolite, monomethyarsonous acid (MMA+3) suppressed erythropoiesis in the bone marrow, beginning at very early stages of erythroid differentiation. We found that As+3 selectively disrupted the function of an essential transcriptional regulator of erythropoiesis, GATA-1. Impairment of GATA-1 resulted from As+3 interaction with the zinc finger motifs of GATA-1, causing an inhibition of erythropoiesis and an imbalance of hematopoietic differentiation.

MMA+3 was also found to impair the differentiation of early erythroid progenitors through the loss of GATA-1 and by the suppression of erythropoietin (EPO)-activated signal transducer and activator of transcription 5 (STAT5) signaling. Disruption of GATA-1 and GATA-1/EPO-activated STAT5 by As+3 and MMA+3, respectively compromised the regulation of a critical prosurvival factor, B-cell lymphoma-extra-large, resulting in the aberrant cell death of early erythroid progenitor cells.

Results from this study clearly demonstrate that early developing erythroid progenitors in the bone marrow are sensitive targets of As+3 and MMA+3 toxicity. MMA+3 was found to be more toxic than As+3 to early erythroid progenitor cells, likely by disrupting multiple pathways necessary for erythropoiesis. For the first time, this study provides novel mechanistic information of arsenic-induced dysregulation and inhibition of erythropoiesis, which is potentially a significant contributing factor to the high incidence of anemia in people chronically exposed to arsenic.

Keywords

Toxicology, Arsenic, Anemia, Hematopoiesis, Erythropoiesis

Document Type

Dissertation

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Dr. Scott W. Burchiel

Second Committee Member

Dr. Ke Jian Liu

Third Committee Member

Dr. Laurie G. Hudson

Fourth Committee Member

Dr. Andrea M. Allan

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