Arsenic-induced bone marrow toxicity: ultrastructural and electron- probe analysis

Abstract

A patient with severe arsenic poisoning that resulted in marked peripheral blood and bone marrow abnormalities, including megaloblastic erythropoiesis experienced many of the previously reported hematologic complications of arsenic poisoning: leukopenia, granulocytopenia, absolute eosinophilia, and profound anemia. In this study we report an ultrastructural and electron-probe analysis of the bone marrow. Although megaloblastic anemia associated with arsenic poisoning has been described rarely, the presence of arsenic in the local bone marrow milieu has not been demonstrated previously. The ultrastructural features of arsenic-induced bone marrow toxicity are similar to those described in other dyserythropoietic states and include marked nuclear aberrations involving shape, chromatin distribution, and nuclear envelope. Using the technique of energy-dispersive x-ray analysis (electron probe) we demonstrated arsenic in bone marrow spicules; this supports the contention that arsenic can cause megaloblastic anemia. We suggest that this technique may be a useful tool in further studies that attempt to explore the mechanism of arsenic-induced hematologic toxicity. Finally, we suggest that arsenic has a direct toxic effect on DNA synthesis that results in marked disturbances of nuclear division. We recommend that the most appropriate screening procedure to evaluate possible arsenic poisoning is tissue arsenic measurements (hair and nails) rather than 24-hr urinary measurements.

Mechanism of arsenic‐induced inhibition of erythropoiesis in mice

“…[ 2 ] . Aberrant DNA synthesis has been implied as a mechanism for the anemia, since megaloblastoid changes, bizarre erythroid morphology, and karyorrhexis have been reported to accompany some cases of arsenic toxicity in man [l- 3,8]. While megaloblastosis and dyserythropoiesis were not found in the marrow of mice in our study, aberrant DNA synthesis was confirmed by the demonstration of decreased H thymidine incorporation into nucleated erythroid cells.…”

Chronic arsenic intoxication diagnostic score (CAsIDS)

“…Chronic eosinophilia and leukopenia have been reported in CAsI (Feussner, Shelburne, Bredehoeft, & Cohen, ; Groch & Heck, ; Sengupta, Saha, Jash, & Bandyopadhyay, ; Vrotsos, Martinez, Pizzolato, Martinez, & Sriganeshan, ). Arsenic may increase the frequency of CD4(+) CD25(+) Foxp3(+) regulatory T cells (Song et al, ), and increased numbers of CD4(+) cells predispose to autoimmune neuritis when these cells are stimulated by proinflammatory mediators such as IFN‐γ (Brunn et al, ).…”

Cellular and Molecular Mechanisms of Environmental Pollutants on Hematopoiesis

“…Epidemiological studies carried out in Bangladesh and Romania, areas characterized by geogenic contamination of underground drinking water, correlated chronic As exposure with anemia [ 251 , 252 , 253 , 254 ]. A case report demonstrated pronounced histological alterations in the BM of a patient suffering from arsenic poisoning, characterized by marked nuclear aberrations involving nucleus shape, chromatin distribution, and nuclear envelope [ 255 ]. In vitro analyses showed that the molecular mechanism for toxicity of arsenic trioxide in erythroleukemic cell lines and on normal hemopoietic progenitor cells (HPCs) involves several pathways, such as inhibition of Stat5 activation and reduced expression of target genes Bcl-X(L) and glycophorin-A; activation of apoptotic mechanisms leading to cleaving of erythroid transcription factors Tal-1 and GATA-1, whose integrity is required for erythroid cell survival and differentiation; and reduced expression of heat shock protein 70, which is required for maintaining GATA-1 integrity [ 256 ].…”