In vivo assessment of the effects of inorganic arsenic, arsenite (As+3), on the bone marrow (BM) immune progenitor cells in mice showed that 300 parts per billion (ppb) As+3 given over 30 days in drinking water, produced a decrease in total BM cells recovered and suppressed the lymphoid (pre-B) but not the myeloid (GM) progenitor cells colony forming units (CFUs). 75 and 300 ppb As+3 also suppressed spleen T-dependent antibody responses. There was no shift in the general markers of early hematopoietic stem cells, CD34 and CD38, or the mesenchymal stem cells, CD105, in the BM. Splenic CD45+ B cells were unaltered. In vitro studies of three inorganic arsenic species and metabolites, As+3, As+5, and monomethylarsonous acid (MMA+3) at low concentrations (5 - 500 nM) determined that As+3 selectively suppressed the lymphoid progenitors at 50 and 500 nM concentrations. MMA+3 (starting at 5nM) also demonstrated concentration-dependent lymphoid toxicity. Dibenzo[def, p]chrysene (DBC) was also suppressive to the BM in vivo, producing about 90% suppression of the lymphoid progenitors at 10 mg/kg given orally over 5 days in pill forms. At much lower (1 mg/kg), 5 day oral cumulative dose, DBC slightly decreased BM cell recovery, resulting in suppression of CFU-B but not CFU-GM. As environmental co-contaminants, As+3 and DBC co-exposure could easily occur. Results from this research suggest that low dose DBC interacts with established no-effect doses (19 and 75 ppb) of As+3 to produce more BM lymphoid suppression that does not necessarily increase with dose in vivo. In vitro studies show similar pattern for As+3-DBC interactions, occurring at lower (0.5 nM), but not at the higher (5 nM) concentration of As+3. The selective targeting of lymphoid progenitors by low dose As+3 and DBC suggest the involvement of an exclusive signaling pathway. B cells require IL-7 signaling for normal development. This study has uncovered the MMA+3 interference with phosphorylation of STAT5 in the IL-7 signaling pathway, and with the induction of PAX5 gene which is required to maintain commitment to the B-lineage. In summary, these studies contribute to our understanding of BM toxicity by environmentally relevant levels of arsenite.
Arsenic, Immunosuppression, Lymphoid progenitors, Stem cells, Monomethylarsounous acid, Dibenzo[def, p]chrysene, Immunotoxicity, Low dose arsenite interactions
National Institute of Health
Level of Degree
Biomedical Sciences Graduate Program
Burchiel, Scott W.
First Committee Member (Chair)
Second Committee Member
Hudson, Laurie G
Third Committee Member
Liu, Ke Jian
Ezeh, Peace Chinyere. "MECHANISMS OF LOW DOSE ARSENIC LYMPHOID STEM CELL IMMUNOTOXICITY AND POTENTIAL INTERACTIONS WITH DIBENZO[def, p]CHRYSENE (DBC)." (2015). http://digitalrepository.unm.edu/biom_etds/123