Persistent Link:
http://hdl.handle.net/10150/204310
Title:
THE EFFECTS OF TRICHLOROETHYLENE ON HEART DEVELOPMENT
Author:
Makwana, Om
Issue Date:
2010
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Embargo:
Embargo: Release after 12/6/2012
Abstract:
Trichloroethylene (TCE; TRI; C2HCl3) is an organic solvent used as an industrial degreasing agent. Due to its widespread use and volatile nature, TCE is a common environmental contaminant. Trichloroethylene exposure has been implicated in the etiology of heart defects in human populations and animal models. Recent data suggest misregulation of Ca2+ homeostasis in a cardiomyocyte cell line after TCE exposure (Caldwell, Thorne et al. 2008). We hypothesized that misregulation of Ca2+ homeostasis alters myocyte function and leads to changes in embryonic blood flow. In turn, changes in cardiac flow are known to cause cardiac malformations. To investigate this hypothesis we dosed developing chick embryos in ovo with environmentally relevant doses of TCE (8 ppb and 800 ppb). We then isolated RNA from embryos at crucial time points in development for real-time PCR analysis of markers for altered blood flow. Based on this analysis, we observed effects on ET-1 (Endothelin-1), NOS-3 (Nitric Oxide Synthase-3) and Krüppel-Like Factor 2 (KLF2) expression relative to TCE exposure. Additionally, we assessed cardiomyocyte function by isolating chick E18 cardiomyocytes from embryos exposed to TCE in ovo. Cells were measured for rate of contraction after pulsing with extracellular Ca2+ and electrical stimulation at a frequency of 1.0 Hz. These functional data showed an effect on Ca2+ handling in cardiomyocytes exposed to TCE. To investigate an apparent non-monotypic effect in the heart where 8 ppb produced a stronger effect than 800 ppb, we isolated RNA from the developing heart and AV Canal to investigate the expression of several candidate Cytochrome P450s (CYPs) related to TCE metabolism. We observed a significant induction of multiple CYP2 family members in the developing heart after low dose TCE exposure. Together, these data suggest cardio-specificity of TCE as a teratogen and may reflect a requirement for normal calcium regulation of contractile function during organ development.
Type:
text; Electronic Dissertation
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cell Biology & Anatomy
Degree Grantor:
University of Arizona
Advisor:
Runyan, Raymond B.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleTHE EFFECTS OF TRICHLOROETHYLENE ON HEART DEVELOPMENTen_US
dc.creatorMakwana, Omen_US
dc.contributor.authorMakwana, Omen_US
dc.date.issued2010-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.releaseEmbargo: Release after 12/6/2012en_US
dc.description.abstractTrichloroethylene (TCE; TRI; C2HCl3) is an organic solvent used as an industrial degreasing agent. Due to its widespread use and volatile nature, TCE is a common environmental contaminant. Trichloroethylene exposure has been implicated in the etiology of heart defects in human populations and animal models. Recent data suggest misregulation of Ca2+ homeostasis in a cardiomyocyte cell line after TCE exposure (Caldwell, Thorne et al. 2008). We hypothesized that misregulation of Ca2+ homeostasis alters myocyte function and leads to changes in embryonic blood flow. In turn, changes in cardiac flow are known to cause cardiac malformations. To investigate this hypothesis we dosed developing chick embryos in ovo with environmentally relevant doses of TCE (8 ppb and 800 ppb). We then isolated RNA from embryos at crucial time points in development for real-time PCR analysis of markers for altered blood flow. Based on this analysis, we observed effects on ET-1 (Endothelin-1), NOS-3 (Nitric Oxide Synthase-3) and Krüppel-Like Factor 2 (KLF2) expression relative to TCE exposure. Additionally, we assessed cardiomyocyte function by isolating chick E18 cardiomyocytes from embryos exposed to TCE in ovo. Cells were measured for rate of contraction after pulsing with extracellular Ca2+ and electrical stimulation at a frequency of 1.0 Hz. These functional data showed an effect on Ca2+ handling in cardiomyocytes exposed to TCE. To investigate an apparent non-monotypic effect in the heart where 8 ppb produced a stronger effect than 800 ppb, we isolated RNA from the developing heart and AV Canal to investigate the expression of several candidate Cytochrome P450s (CYPs) related to TCE metabolism. We observed a significant induction of multiple CYP2 family members in the developing heart after low dose TCE exposure. Together, these data suggest cardio-specificity of TCE as a teratogen and may reflect a requirement for normal calcium regulation of contractile function during organ development.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineCell Biology & Anatomyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorRunyan, Raymond B.en_US
dc.contributor.committeememberSelmin, Ornellaen_US
dc.contributor.committeememberBoitano, Scotten_US
dc.contributor.committeememberLantz, R. Clarken_US
dc.identifier.proquest11381-
dc.identifier.oclc752261247-
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