Biomedical Sciences ETDs

Publication Date

Spring 3-1-2017

Abstract

Arsenic, a ubiquitous environmental contaminant, is known to cause immunotoxicity. However, the mechanisms of arsenic induced immunotoxicity are still not clear. Arsenite (As+3), the trivalent inorganic form of arsenic, was found to increase DNA damage and inhibit PARP activity in thymus cells at 50 nM in vitro. Oxidative stress and double strand breaks (DSBs) formation occurred in thymus cells exposed to As+3 at 500 nM. The genotoxicity was found to be related to As+3 exporter expressions and reversed by zinc supplement. IL-7 signaling, the critical cytokine signal for the early DN thymic T cell proliferation, was found to be suppressed by As+3 at 500 nM and MMA+3 at 50 nM in vitro. The suppressive effects reduced the cell cycle gene expression.

After 30 d in vivo exposure of up to 500 parts per billion (ppb) As+3, thymus cells were found to contain the higher levels of arsenic than bone marrow and spleen cells. Correlations between intracellular arsenic concentrations and the increase of DNA damage were found in both the bone marrow and thymus, but not the spleen. Monomethylarsonous acid (MMA+3) was also found to be more genotoxic than As+3 in vitro in bone marrow, spleen and thymus, and was demonstrated to be the most prevalent form of arsenic in bone marrow and thymus after in vivo exposures.

Benzo(a) pyrene-7,8-dihydrodiol (BP-diol), the metabolite of benzo(a) pyrene (BaP) was found to interact with As+3 synergistically at low concentrations to increase the DNA damage and inhibit PARP activity in primary thymus cells. The interactive effects were also demonstrated to increase the expression of CYP1A1 and CYP1B1, two critical enzymes for the metabolism of BP-diol to the DNA adduct forming compound, benzo(a) pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE).

The differential sensitivity to As+3 of double negative (DN) and double positive (DP) thymus cell subsets was also evaluated and compared. Higher intracellular accumulation of As+3 was found in DN cells, with the higher DNA damage than DP cells after in vitro As+3 treatments. The expressions of two As+3 exporters, Mdr1 and Mrp1, were shown to be inversely correlated with the selective genotoxicity in DN cells.

These studies contributed to our understanding of the mechanisms associated with the toxicity induced by environmentally relevant concentrations of arsenic and its potential interactions with other environmental contaminants.

Keywords

Arsenic, Thymus, Mechanisms of immunotoxicity, Interactive toxicity, Arsenic transportation, IL-7 signaling

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Scott W Burchiel

Second Committee Member

Ke Jian Liu

Third Committee Member

Laurie G Hudson

Fourth Committee Member

Xuexian Yang

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