Involvement of the estrogen receptor and aryl hydrocarbon receptor in 4-vinylcyclohexene diepoxide-induced ovotoxicity in F344 rats

Persistent Link:
http://hdl.handle.net/10150/279855
Title:
Involvement of the estrogen receptor and aryl hydrocarbon receptor in 4-vinylcyclohexene diepoxide-induced ovotoxicity in F344 rats
Author:
Thompson, Kary Ellen
Issue Date:
2001
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.
Abstract:
Women are born with a finite number of primordial follicles, the smallest follicles in the ovary. Once these follicles are destroyed, they cannot be replaced and after extensive loss, ovarian failure (menopause) can occur. The industrial chemical 4-vinylcyclohexene diepoxide (VCD) induces depletion of these follicles and causes premature ovarian failure in rats. VCD-induced ovotoxicity has been found to accelerate a natural process in the ovary, atresia, which occurs via apoptosis. The mechanism(s) by which VCD enhances follicular atresia are unknown; however, it has been shown to alter the expression of several genes and proteins associated with apoptosis. While downstream signaling events of VCD are becoming identified, the early signaling events of this pathway have not yet been determined, but may involve a receptor-mediated cascade. Therefore, these studies tested the hypothesis that VCD-induced ovotoxicity involves a nuclear receptor-mediated pathway that leads to increased atresia. Concurrent treatment of rats with VCD and estradiol selectively protected primary follicles from loss by an estrogen receptor-mediated mechanism via a reduction of caspase-3-induced apoptosis. VCD does not alter ER number, affinity, circulating estradiol levels, or directly bind ERbeta. Concurrent dosing of rats with VCD and an AhR antagonist prevented primordial and primary follicle loss via a reduction in caspase-3-induced apoptosis. Repeated dosing with VCD was shown to up-regulate expression of AhR mRNA; however, VCD did not alter expression of AhR-mediated genes glutathione-S-transferase Ya1 or Ya2 nor CYP 1A1 protein. AhR-deficient mice were still susceptible to VCD-induced follicle loss. Repeated dosing with VCD reduced Heat Shock Protein (HSP) 90 expression in small primary follicles. Analogs of the ER and AhR did not alter HSP90 protein, nor did a loss of HSP90 function induce follicle loss or potentiate VCD-induced follicle depletion. While the ER, AhR, and HSP90 are all co-localized in the oocyte nucleus of primordial and primary follicles, no evidence was seen to support that these proteins are interacting. Taken together, the ER is able to prevent VCD-induced ovotoxicity in primary follicles, the AhR is not required for VCD-induced follicle loss, and HSP90 does not appear to play a central role in follicle depletion caused by VCD.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Toxicology.; Biology, Animal Physiology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Physiological Sciences
Degree Grantor:
University of Arizona
Advisor:
Hoyer, Patricia B.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleInvolvement of the estrogen receptor and aryl hydrocarbon receptor in 4-vinylcyclohexene diepoxide-induced ovotoxicity in F344 ratsen_US
dc.creatorThompson, Kary Ellenen_US
dc.contributor.authorThompson, Kary Ellenen_US
dc.date.issued2001en_US
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.abstractWomen are born with a finite number of primordial follicles, the smallest follicles in the ovary. Once these follicles are destroyed, they cannot be replaced and after extensive loss, ovarian failure (menopause) can occur. The industrial chemical 4-vinylcyclohexene diepoxide (VCD) induces depletion of these follicles and causes premature ovarian failure in rats. VCD-induced ovotoxicity has been found to accelerate a natural process in the ovary, atresia, which occurs via apoptosis. The mechanism(s) by which VCD enhances follicular atresia are unknown; however, it has been shown to alter the expression of several genes and proteins associated with apoptosis. While downstream signaling events of VCD are becoming identified, the early signaling events of this pathway have not yet been determined, but may involve a receptor-mediated cascade. Therefore, these studies tested the hypothesis that VCD-induced ovotoxicity involves a nuclear receptor-mediated pathway that leads to increased atresia. Concurrent treatment of rats with VCD and estradiol selectively protected primary follicles from loss by an estrogen receptor-mediated mechanism via a reduction of caspase-3-induced apoptosis. VCD does not alter ER number, affinity, circulating estradiol levels, or directly bind ERbeta. Concurrent dosing of rats with VCD and an AhR antagonist prevented primordial and primary follicle loss via a reduction in caspase-3-induced apoptosis. Repeated dosing with VCD was shown to up-regulate expression of AhR mRNA; however, VCD did not alter expression of AhR-mediated genes glutathione-S-transferase Ya1 or Ya2 nor CYP 1A1 protein. AhR-deficient mice were still susceptible to VCD-induced follicle loss. Repeated dosing with VCD reduced Heat Shock Protein (HSP) 90 expression in small primary follicles. Analogs of the ER and AhR did not alter HSP90 protein, nor did a loss of HSP90 function induce follicle loss or potentiate VCD-induced follicle depletion. While the ER, AhR, and HSP90 are all co-localized in the oocyte nucleus of primordial and primary follicles, no evidence was seen to support that these proteins are interacting. Taken together, the ER is able to prevent VCD-induced ovotoxicity in primary follicles, the AhR is not required for VCD-induced follicle loss, and HSP90 does not appear to play a central role in follicle depletion caused by VCD.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Toxicology.en_US
dc.subjectBiology, Animal Physiology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHoyer, Patricia B.en_US
dc.identifier.proquest3031360en_US
dc.identifier.bibrecord.b42283383en_US
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