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.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-6286 |
| Date | 01 December 2015 |
| Creators | Xin, Xing |
| Contributors | Ludewig, Gabriele, Schnoor, Jerald L. |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright 2015 Xing Xin |
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