Biomedical Sciences ETDs

Publication Date

5-1-2015

Abstract

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.

Keywords

Arsenic, Immunosuppression, Lymphoid progenitors, Stem cells, Monomethylarsounous acid, Dibenzo[def, p]chrysene, Immunotoxicity, Low dose arsenite interactions

Sponsors

National Institute of Health

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Burchiel, Scott W.

First Committee Member (Chair)

Beswick, Ellen

Second Committee Member

Hudson, Laurie G

Third Committee Member

Liu, Ke Jian

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