Arsenite and monomethylarsonous acid disrupt erythropoiesis through combined effects on differentiation and survival pathways in early erythroid progenitors. (10th October 2021)

• Record Type: Journal Article
• Authors: Medina, Sebastian; Bolt, Alicia M.; Zhou, Xixi; Wan, Guanghua; Xu, Huan; Lauer, Fredine T.; Liu, Ke Jian; Burchiel, Scott W.
• Is Part Of: Toxicology letters. Volume 350(2021)
• Page Start: 111
• Page End: 120
• Publication Date: 2021-10-10
• Subjects: Arsenic -- Arsenite (As+3) -- Monomethylarsonous acid (MMA+3) -- Erythropoiesis -- STAT5 -- GATA-1; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2021.07.008
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: Development of early-stage erythroid progenitors is impaired by both As +3 and MMA +3 . As +3 and MMA +3 disrupt the differentiation and survival of early erythroid progenitors. Differentiation and survival were impaired by combined effects on GATA-1 and STAT5. MMA +3 is more toxic in vitro than As +3 to early developing erythroid cells. Abstract: Strong epidemiological evidence demonstrates an association between chronic arsenic exposure and anemia. We recently found that As +3 impairs erythropoiesis by disrupting the function of GATA-1; however the downstream pathways impacted by the loss of GATA-1 function have not been evaluated. Additionally, our previous findings indicate that the predominant arsenical in the bone marrow of mice exposed to As +3 in their drinking water for 30 days was MMA +3, but the impacts of this arsenical on erythorpoisis also remain largely unknown. The goal of this study was to address these critical knowledge gaps by evaluating the comparative effects of arsenite (As +3 ) and the As +3 metabolite, monomethyarsonous acid (MMA +3 ) on two critical regulatory pathways that control the differentiation and survival of early erythroid progenitor cells. We found that 500 nM As +3 and 100 and 500 nM MMA +3 suppress erythropoiesis by impairing the differentiation of early stage erythroid progenitors. The suppression of early erythroid progenitor cell development was attributed to combined effects on differentiation and survival pathways mediated by disruption of GATA-1 and STAT5. Our results show that As +3 primarily disrupted GATA-1 function; whereas, MMA +3 suppressed both GATA-1 and STAT5 activity. Collectively, these findings provide novel mechanistic insights into arsenic-induced dyserythropoiesis and suggest that MMA +3 may be more toxic than As +3 to early developing erythroid cells.