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Disruption of angiogenesis by methyl tert-butyl ether (MTBE) is mediated by a dysregulation of the vascular endothelial growth factor (VEGF) pathway
Descriptive
TitleInfo
Title
Disruption of angiogenesis by methyl tert-butyl ether (MTBE) is mediated by a dysregulation of the vascular endothelial growth factor (VEGF) pathway
Name
(type = personal)
NamePart
(type = family)
Bonventre
NamePart
(type = given)
Josephine Ann
NamePart
(type = date)
1982-
DisplayForm
Josephine Bonventre
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
NamePart
(type = family)
Cooper
NamePart
(type = given)
Keith R.
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Keith R. Cooper
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Advisory Committee
Role
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(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
White
NamePart
(type = given)
Lori A.
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Lori A. White
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Advisory Committee
Role
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(authority = RULIB)
internal member
Name
(type = personal)
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(type = family)
Reuhl
NamePart
(type = given)
Kenneth
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Kenneth Reuhl
Affiliation
Advisory Committee
Role
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(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Richardson
NamePart
(type = given)
Jason R.
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Jason R. Richardson
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Gordon
NamePart
(type = given)
Marion K.
DisplayForm
Marion K. Gordon
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
McElroy
NamePart
(type = given)
Anne E.
DisplayForm
Anne E. McElroy
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
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(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2012
DateOther
(qualifier = exact);
(type = degree)
2012-10
CopyrightDate
(qualifier = exact)
2012
Place
PlaceTerm
(type = code)
xx
Language
LanguageTerm
(authority = ISO639-2b);
(type = code)
eng
Abstract
(type = abstract)
Vascular endothelial growth factor (VEGF) is an essential mitogenic factor required for normal angiogenesis. In development, the primary inducer of this protein is hypoxia via hypoxia inducible factors (HIFs). Methyl tert-butyl ether (MTBE) was hypothesized to disrupt angiogenesis by altering the HIF-VEGF pathway. Exposure of zebrafish embryos to MTBE caused vascular lesions, specifically pooled blood in the common cardinal vein (CCV), cranial hemorrhages, and abnormal intersegmental vessels (ISV). These lesions occurred throughout development and were preceded by a critical period between 6-somites and Prim-5 stages during which there was a significant decrease in mRNA transcript levels of vegf-a, vegf-c and vegf receptor 2 (vegfr2). Lesions other than those associated with the vasculature were not observed. Embryonic exposure to the two primary metabolites, tert-butyl alcohol and formaldehyde, did not induce vascular lesions, indicating the parent chemical was responsible for the anti-angiogenesis. When embryos were exposed to two structurally related chemicals, ethyl tert-butyl ether iii (ETBE) or tert-amyl methyl ether (TAME), some vascular lesions were observed, but zebrafish also exhibited lesions in the heart, whole body edema, and craniofacial abnormalities. Unlike MTBE, ETBE, and TAME exposure did not significantly alter vegf expression. Of the 3 structurally similar ethers, MTBE appears unique in its ability to target developing endothelial cells. An analysis of the global gene expression changes in zebrafish exposed to MTBE during the critical period identified the cardiovascular system was among the most altered pathways affected by MTBE toxicity. Finally, manipulation of the HIF-VEGF pathway to rescue the specific MTBE-induced vascular lesions, via an over-expression of vegf-a and inhibition of HIF degradation, convincingly demonstrated that MTBE toxicity is mediated by the down regulation of VEGF at a critical time during cardiovascular development. Understanding the underlying mechanisms of angiogenesis is important to developing new therapies used to quell solid tumor growth, enhance wound repair, and reduce diabetes induced vascular damage, among others. Chemicals with anti-angiogenic properties, such as MTBE, can be used to advance the science of angiogenesis in both a disease state and during development.
Subject
(authority = RUETD)
Topic
Environmental Sciences
Subject
(authority = ETD-LCSH)
Topic
Neovascularization inhibitors
Subject
(authority = ETD-LCSH)
Topic
Butyl methyl ether
Subject
(authority = ETD-LCSH)
Topic
Neovascularization
RelatedItem
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
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ETD
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
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rucore19991600001
Identifier
ETD_4202
Identifier
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http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000066637
PhysicalDescription
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electronic resource
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application/pdf
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text/xml
Extent
xxi, 190 p. : ill.
Note
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Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = statement of responsibility)
by Josephine Ann Bonventre
Location
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(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T33F4NFQ
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
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The author owns the copyright to this work.
RightsHolder
(type = personal)
Name
FamilyName
Bonventre
GivenName
Josephine
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
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(qualifier = exact);
(point = start)
2012-08-24 23:21:57
AssociatedEntity
Name
Josephine Bonventre
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
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
DateTime
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(qualifier = exact);
(point = start)
2012-10-31
DateTime
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(qualifier = exact);
(point = end)
2013-05-02
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 2nd, 2013.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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3302400
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