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Placentation and barrier transporters: regulation by endogenous and exogenous factors

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TitleInfo
Title
Placentation and barrier transporters: regulation by endogenous and exogenous factors
Name (type = personal)
NamePart (type = family)
Gorczyca
NamePart (type = given)
Ludwik Janusz
NamePart (type = date)
1991-
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Ludwik Janusz Gorczyca
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Aleksunes
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Lauren
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Lauren Aleksunes
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Advisory Committee
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chair
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Buckley
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Brian
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Brian Buckley
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Advisory Committee
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RoleTerm (authority = RULIB)
internal member
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Guo
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Grace
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Grace Guo
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Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Stapleton
NamePart (type = given)
Phoebe
DisplayForm
Phoebe Stapleton
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Fortin
NamePart (type = given)
Marie
DisplayForm
Marie Fortin
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
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
Genre (authority = ExL-Esploro)
ETD doctoral
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2020
DateOther (type = degree); (qualifier = exact); (encoding = w3cdtf)
2020-10
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2020
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract (type = abstract)
During pregnancy, the placenta serves as a critical interface between the fetal and maternal circulations and facilitates nutrient-waste exchange to support normal fetal development. Once established, the placenta regulates hormone secretion, xenobiotic metabolism, and expression of transporters to maintain overall barrier integrity. Uptake and efflux transporters are localized to the syncytiotrophoblast cells and in part regulate the disposition of endogenous signaling molecules, hormones, chemicals, and drugs across the placenta. Development of the placenta can be affected by both endogenous (i.e. low oxygen, cyclic nucleotide signaling) and xenobiotic (i.e. mycotoxin zearalenone) influences. Due to the critical role of the placenta in supporting normal fetal development, more work is urgently needed to further characterize its physiology and susceptibility to insults. The purpose of this dissertation was to investigate the impact of endogenous (i.e. hypoxia, cyclic nucleotide signaling) and exogenous (i.e. zearalenone) factors on placentation with a focus on endobiotic and xenobiotic disposition through transporter-mediated mechanisms. Physiologically relevant low oxygen tension, observed during the 1st and 2nd trimesters, altered the transcriptional regulatory pathways and drug transporter profiles in two in vitro placental models (BeWo choriocarcinoma cells, human placental explants). Altered functionality of drug transporters may not only impact the disposition of xenobiotics but also endogenous molecules that activate/regulate downstream signaling cascades and overall placentation. Cyclic adenosine monophosphate (cAMP)-mediated signaling regulates the process of syncytialization whereby giant multinucleated syncytiotrophoblasts arise from the fusion of progenitor cytotrophoblast cells. Multidrug resistance-associated protein (MRP) transporters are localized to the syncytiotrophoblast cell layer and regulate intracellular cAMP levels through active efflux. Studies using both pharmacological and genetic loss-of-function approaches targeting the MRP5 transporter revealed enhanced intracellular concentration of cAMP and syncytialization in placental explants and/or BeWo cells. Zearalenone, an estrogenic mycotoxin, is a known substrate of the BCRP efflux drug transporter. In vivo studies using Bcrp heterozygous mice demonstrated that zearalenone increased maternal weight gain and embryo resorption as well as decreased placental weight and area. Further examination revealed that markers responsible for placental differentiation were globally down-regulated in zearalenone-treated placentas. Zearalenone exposure differentially regulated placental xenobiotic transporter expression and decreased placental antioxidant defense genes. Together, these data demonstrate that endogenous and exogenous factors may influence placental transporter expression and function, and in turn, lead to altered disposition of endobiotics and xenobiotics and impact placenta and fetal development.
Subject (authority = local)
Topic
Placenta
Subject (authority = RUETD)
Topic
Toxicology
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_11197
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application/pdf
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text/xml
Extent
1 online resource (xx, 433 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier (type = doi)
doi:10.7282/t3-8zww-xz89
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Gorczyca
GivenName
Ludwik
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2020-09-24 13:36:22
AssociatedEntity
Name
Ludwik Gorczyca
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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.
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Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2020-10-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2022-10-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 31st, 2022.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2020-10-01T18:52:27
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2020-10-01T18:52:27
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