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The development of a model of PhIP-induced colon carcinogenesis in CYP1A2-humanized mice
Descriptive
TypeOfResource
Text
TitleInfo
Title
The development of a model of PhIP-induced colon carcinogenesis in CYP1A2-humanized mice
Identifier
ETD_2631
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000053614
Identifier
(type = doi)
doi:10.7282/T37W6C8N
Language
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(authority = ISO 639-3:2007);
(type = text)
English
Genre
(authority = marcgt)
theses
Subject
(authority = RUETD)
Topic
Cell and Developmental Biology
Subject
(authority = ETD-LCSH)
Topic
Transgenic mice--Diseases
Subject
(authority = ETD-LCSH)
Topic
Colon (Anatomy)--Cancer--Pathophysiology
Subject
(authority = ETD-LCSH)
Topic
Colon (Anatomy)--Cancer--Prevention
Subject
(authority = ETD-LCSH)
Topic
Heterocyclic chemistry
Subject
(authority = ETD-LCSH)
Topic
Cytochrome P-450--Physiological effect
Abstract
(type = abstract)
The dietary carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) is considered one of the most abundant heterocyclic amines formed during the cooking of meats and fish. PhIP is metabolically activated to its carcinogenic form primarily by the human Cytochrome P450 enzyme, CYP1A2; whereas in rodents, PhIP is detoxified by the Cyp1a2 mouse ortholog. This metabolic activation is followed by esterification to produce activated esters that can bind to DNA to form adducts. PhIP-DNA adducts have been identified in various tissues of mice and in the colon of humans. PhIP has also demonstrated carcinogenicity in rodents, preferentially in the colons of rats and lymphatic system of mice. Through the use of a recently generated transgenic mouse model consisting of a human CYP1A1/1A2 gene insert on a mouse Cyp1a1/1a2 knockout background, we have developed a PhIP-induced humanized model of colon carcinogenesis. Male and female hCYP1A2 mice were given various combinations of PhIP (100mg/kg or 200mg/kg) by oral gavage without or with DSS (1% or 1.5%) in the drinking water for one week. We observed a single dose of PhIP (200mg/kg) followed by one week administration of dextran sodium sulfate (1.5%) in the drinking water of the hCYP1A2 mice to be the most effective treatment combination to induce colonic adenocarcinomas, with cancer formation in 6 weeks. In other treatment groups, ACF's were found to be present in the colons of mice treated with 100mg/kg of PhIP + 1% DSS as early as 6 weeks and in mice treated with 200mg/kg of PhIP without DSS as early as 12 weeks. In contrast, colonic neoplasms were not observed in C57BL/6J wild-type mice in any of the treatment groups. Pathological analysis of colonic tissue from hCYP1A2 mice treated with 200mg/kg of PhIP + 1.5% DSS revealed severe inflammation, a hyperplastic epithelial lining and an infiltration of leukocytes in the submucosal layer of the colon. Immunohistochemical analysis indicated that colonic neoplasms were associated with nuclear accumulation of β-catenin resembling mutations commonly found in human colon neoplasms. These results suggest that PhIP in combination with DSS in the hCYP1A2 mice is a good short-term animal model to study colon carcinogenesis.
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electronic resource
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xv, 75 p. : ill.
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Note
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M.S.
Note
Includes abstract
Note
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Includes bibliographical references
Note
(type = statement of responsibility)
by Shea Loy
Name
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Loy
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Shea
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1986-
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author
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Shea Loy
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yang
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chung s
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chair
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Advisory Committee
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chung s yang
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Suh
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Nanjoo
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internal member
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Advisory Committee
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Nanjoo Suh
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Zhou
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Renping
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internal member
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Advisory Committee
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Renping Zhou
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Conney
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Allan H
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Advisory Committee
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Allan H Conney
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Rutgers University
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Graduate School - New Brunswick
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2010
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2010
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xx
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Rutgers University Electronic Theses and Dissertations
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ETD
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Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
(type = local)
rucore19991600001
Genre
(authority = ExL-Esploro)
ETD graduate
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Rights
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The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
RightsHolder
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(type = personal)
Name
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Loy
GivenName
Shea
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Permission or license
DateTime
2010-04-15 12:59:47
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Name
Shea Loy
Affiliation
Rutgers University. Graduate School - New Brunswick
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
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Type
Embargo
DateTime
2010-05-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after November 30th, 2010.
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