Defining the Roles of Biotransformation in Arsenic-Induced Hematotoxicity

University Of New Mexico Health Scis Ctr, Albuquerque NM

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Abstract

Anemia adversely impacts the health of approximately 2 billion people worldwide. Growing epidemiologic evidence links chronic arsenic exposure to elevated anemia risk, yet the underlying mechanisms remain poorly understood. Recent work from our group and others has demonstrated that arsenic exposure disrupts red blood cell (RBC) development by impairing zinc finger transcription factors, including GATA-1 and GATA-2, which are essential for early RBC lineage commitment and differentiation. Our findings further show that monomethylarsonous acid (MMAIII), a highly reactive metabolite of inorganic arsenite (AsIII), preferentially accumulates in the bone marrow and more potently suppresses RBC lineage commitment than its inorganic precursor. MMAIII is generated through biotransformation mediated by arsenic (+3 oxidation state) methyltransferase (As3MT), an enzyme primarily expressed in the liver. This suggests that hepatic biotransformation plays a critical role in shaping the systemic distribution and hematopoietic toxicity of arsenic metabolites. While these findings establish a key link between arsenic exposure, GATA factor disruption, and anemia, critical gaps remain in understanding how arsenic biotransformation, tissue-specific distribution of arsenical species, and transcriptional dysregulation converge to drive hematopoietic dysfunction. Our central hypothesis is that tissue-specific differences in arsenic exposure, driven by differential biotransformation and selective metabolite deposition, disrupt the transcriptional landscape of hematopoietic stem and progenitor cells (HSPCs), leading to altered lineage fate decisions, impaired differentiation, and hematopoietic dysfunction. The studies proposed in Aim 1 will define how systemic deposition and local biotransformation shape the distribution of arsenical species in the bone marrow and spleen, the primary and extramedullary sites of hematopoiesis, using spatial and quantitative arsenic mapping in wild-type, As3MT-knockout, and humanized As3MT mice. Aim 2 will investigate how arsenic exposure disrupts transcriptional programs governing lineage commitment by applying single-cell RNA sequencing and chromatin immunoprecipitation followed by sequencing to purified HSPCs from both mouse models and human primary cells. Aim 3 will evaluate zinc supplementation as a targeted intervention strategy to determine whether restoring transcriptional regulation can mitigate arsenic-induced hematopoietic dysfunction. Together, these studies will integrate molecular, transcriptional, and spatial data across As3MT models to define how arsenic biotransformation contributes to tissue-specific hematopoietic toxicity. Findings will inform the development of precision intervention strategies that account for variability in arsenic biotransformation and individual susceptibility to arsenic-induced blood disorders.