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Predicting Biological Degradation and Toxicity of Steroidal Estrogens

Barr, William (2012) Predicting Biological Degradation and Toxicity of Steroidal Estrogens. Master's Thesis, University of Pittsburgh.

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    Abstract

    This study was to construct a model to predict a variety of biological transformations of Ethinylestradiol (EE2) using electronic theory and to analyze the estrogenic potential of EE2 and its metabolites. As a secondary goal, Frontier Electron Density (FED) theory was applied to the natural steroidal estrogens, estrone (E1), estradiol (E2) and estriol (E3) to determine if similar initiating reactions could be expected. Electron density profiles were calculated for EE2 metabolites to determine possible metabolic pathways up to the cleavage of the first ring. The pathways predicted in this study assume that enzymes commonly found in wastewater treatment systems will be available to attack EE2 and each metabolite. Predictive pathways were generated for EE2 based on the electron density and well established degradation rules. A number of metabolites were shown to be consistent with FED theory. There are many methods available for effectively calculating the electron density of a given molecule. Calculations were carried out on the Pittsburgh Supercomputer (PSC) using the computational chemistry software Gaussian 03. Two molecular orbital theories available for use in Gaussian 03 were used and results compared to determine if the level of theory significantly affected the accuracy of the electron density calculations. In the beginning of this study only one theory was used but after studying the available theories in more detail I implemented a theory that was shown to be more accurate in literature. Using this information and well established degradation rules, metabolic pathways leading up to the first ring cleavage were predicted. Experimentally measured metabolites appear in the predicted pathways. In order to evaluate the environmental impacts of steroidal estrogens and their subsequent metabolites the estrogenic potential is calculated using chemaxon software. The estrogenic potential was estimated for EE2 and each of its metabolites both predicted and experimental as well as E1, E2 and E3 and known experimentally measured metabolites that are similar to EE2. In all cases the estrogenic potential of the metabolites indicate that they have a lower toxicity than the parent compounds but may still retain estrogenic potential after biotransformation.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairHarper, Williewharper@pitt.edu
    Committee MemberMonnell, Jasonjdm49@pitt.edu
    Committee MemberKhanna, Vikaskhannav@pitt.edu
    Title: Predicting Biological Degradation and Toxicity of Steroidal Estrogens
    Status: Published
    Abstract: This study was to construct a model to predict a variety of biological transformations of Ethinylestradiol (EE2) using electronic theory and to analyze the estrogenic potential of EE2 and its metabolites. As a secondary goal, Frontier Electron Density (FED) theory was applied to the natural steroidal estrogens, estrone (E1), estradiol (E2) and estriol (E3) to determine if similar initiating reactions could be expected. Electron density profiles were calculated for EE2 metabolites to determine possible metabolic pathways up to the cleavage of the first ring. The pathways predicted in this study assume that enzymes commonly found in wastewater treatment systems will be available to attack EE2 and each metabolite. Predictive pathways were generated for EE2 based on the electron density and well established degradation rules. A number of metabolites were shown to be consistent with FED theory. There are many methods available for effectively calculating the electron density of a given molecule. Calculations were carried out on the Pittsburgh Supercomputer (PSC) using the computational chemistry software Gaussian 03. Two molecular orbital theories available for use in Gaussian 03 were used and results compared to determine if the level of theory significantly affected the accuracy of the electron density calculations. In the beginning of this study only one theory was used but after studying the available theories in more detail I implemented a theory that was shown to be more accurate in literature. Using this information and well established degradation rules, metabolic pathways leading up to the first ring cleavage were predicted. Experimentally measured metabolites appear in the predicted pathways. In order to evaluate the environmental impacts of steroidal estrogens and their subsequent metabolites the estrogenic potential is calculated using chemaxon software. The estrogenic potential was estimated for EE2 and each of its metabolites both predicted and experimental as well as E1, E2 and E3 and known experimentally measured metabolites that are similar to EE2. In all cases the estrogenic potential of the metabolites indicate that they have a lower toxicity than the parent compounds but may still retain estrogenic potential after biotransformation.
    Date: 30 January 2012
    Date Type: Publication
    Defense Date: 15 November 2011
    Approval Date: 30 January 2012
    Submission Date: 23 November 2011
    Release Date: 30 January 2012
    Access Restriction: No restriction; Release the ETD for access worldwide immediately.
    Patent pending: No
    Number of Pages: 87
    Institution: University of Pittsburgh
    Thesis Type: Master's Thesis
    Refereed: Yes
    Degree: MS - Master of Science
    Additional Information: The document itself counting copyright and thesis data (counted as roman numerals) is 101 pages. The actual thesis is 87 pages
    Uncontrolled Keywords: ethinylestradiol, molecular orbital theory, estrogenicity, human estrogen receptor, biodegradation, estrogen receptor enzyme
    Schools and Programs: Swanson School of Engineering > Civil and Environmental Engineering
    Date Deposited: 30 Jan 2012 16:26
    Last Modified: 16 Jul 2014 17:03

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