2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is persistent in the environment and the food chain resulting in a chronic exposure to human populations. The effects of this known human carcinogen are evaluated by measuring various TCDD-inducible endpoints. Cytochrome P450 1B1, a recently identified TCDD responsive gene, shows inducibility in both the rat and humans that is similar to Cytochrome P450 1A1, a widely accepted marker for TCDD responsiveness. In order to evaluate a Sprague Dawley rat model to predict human tissue effects with easily accessible human tissue, such as peripheral blood lymphocytes (PBLs), rat PBL and granulocyte CYP1B1 and CYP1A1 expression were compared to expression among several tissues. Two treatment groups were used: an acute group, dosed with a 540 ng/kg single daily dose over a 3-day period followed by a day 4 sacrifice, and a chronic group, dosed biweekly with 7.6 ng/kg/day for 15 weeks. Competitive quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to show the different levels of expression of CYP1B1 and CYP1A1 in resting PBLs, granulocytes and various other tissues. CYP1B1 and CYP1A1 were shown to be inducible in liver, adrenal gland, lung, kidney, granulocytes and in PBLs. However, a lower induction for PBLs and granulocytes was observed compared to the highly inducible tissues such as liver and lung. Furthermore, male rats showed a 200-fold induction in CYP1B1 expression in PBLs and 16-fold induction in granulocytes in the chronic group following TCDD exposure compared to a 2 fold induction in PBLs and 2-fold induction in granulocytes for the female rats of the same dosing group. The differences in inducibility between PBLs, granulocytes and tissue may be due to the different levels of TCDD that reach each tissue due to the pharmacokinetics dependent upon that tissue. With the different expression patterns and low copy number of CYP1B1 and CYP1A1 in PBLs and granulocytes in Sprague Dawley rats, their use as surrogates for expression in tissues of interest does not correlate with recent published data for human studies on PBLs exposed to TCDD. Therefore, the comparison needs to be further investigated and the use of PBLs better established as a surrogate for expression.
| Identifer | oai:union.ndltd.org:NCSU/oai:NCSU:etd-04292005-105927 |
| Date | 02 May 2005 |
| Creators | Miller, Brian Douglas |
| Contributors | James N. Petitte, John F. Roberts, Randy L. Rose |
| Publisher | NCSU |
| Source Sets | North Carolina State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://www.lib.ncsu.edu/theses/available/etd-04292005-105927/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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