Document Type

Dissertation

Date of Degree

Fall 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Human Toxicology

First Advisor

Gabriele Ludewig

Second Advisor

Jerald Schnoor

Abstract

Polychlorinated biphenyls (PCBs) are synthetic persistent organic compounds that are known to be carcinogenic to humans. Changes in telomerase activity and telomere length are hallmarks of aging and carcinogenesis. Retention of telomerase activity and long telomeres are key characteristics of stem cells and progenitor cells. I hypothesize that PCBs modulate telomerase activity and telomeres of hematopoietic stem cells and progenitor cells via interference of gene regulation and potentially disrupt cell differentiation. To investigate this possibility, I used progenitor-like cells, human promyelocytic leukemia cells (HL-60), and stem cells from rat bone marrow. I show that PCB126 and PCB153 display toxic effects on telomerase activity, telomere length and their related gene expression in progenitor-like HL-60 cells, but they did not exert much effect on differentiation. Further, an in vivo/in vitro study using rat bone marrow cells shows that PCB126-induced hematotoxicity, evidenced by reduction in telomerase activity and TERT gene expression, an increase of the differentiation and a change in the differentiation direction towards granulocytes, which indicate an effect on stem cell function. I also show that the most potent dioxin-like congener, PCB126, regulates hTERT gene expression by activation of the AhR pathway. Both AhR and ARNT work together as a repressor of hTERT transcription. This research improves our understanding of mechanisms of PCB126 and PCB153 toxicity on hematopoietic stem cells and progenitor cells, which will ultimately have significant implications for human health.

Public Abstract

Polychlorinated biphenyls (PCBs) are synthetic organic compounds that resist natural breakdown in the environment. They have various adverse health effects to humans including causing cancers. Telomerase and telomeres are an enzyme complex and DNA structures, respectively, whose functions are highly correlated with aging and cancer. Activated telomerase enzyme and long telomeres are key characteristics of stem cells and progenitor cells. These cells play an important role in repairing our organs and tissues. Aging of stem cells is associated with many adverse health effects including aging and cancer. This dissertation research used two cell models, human progenitor-like cells in culture and rat bone marrow stem cells exposed to PCBs, to investigate the effects of PCBs on stem cells and progenitor cells. My results show that PCBs are toxic to these cells by changing telomerase activity and disturbing telomeres and their maintenance, which can consequently affect the function of these cells. This research improves our understanding of toxicity of PCBs on stem cells and progenitor cells, which may have significant implications for human health.

Keywords

publicabstract, PCBs, Stem cells, Telomerase, Telomeres

Pages

xiii, 114 pages

Bibliography

Includes bibliographical references (pages 102-114).

Copyright

Copyright 2015 Xing Xin

Included in

Toxicology Commons

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