DOI

10.17077/etd.1k67199t

Document Type

Dissertation

Date of Degree

Fall 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

Gloer, James B.

Second Advisor

Cwiertny, David M.

First Committee Member

Wiemer, David F.

Second Committee Member

Stone, Elizabeth A.

Third Committee Member

Forbes, Tori Z.

Abstract

For bioactive chemical classes, it is often assumed that environmental transformation eliminates associated ecosystem risks. However, for endocrine-active steroid hormones, modest changes in structure can have a significant influence on biological activity and thus, subtle environmental transformations can yield products with conserved, enhanced, or activity across different biological endpoints.

The aim of this work was to explore the environmental fate of high potency, endocrine-active steroid hormones during natural or engineered water processes in order to test the hypothesis that steroid transformation products generated during these processes are likely to contribute to residual bioactivity often reported in water resources. Specifically, laboratory experiments were used to simulate chemical disinfection (e.g., chlorination) or natural processes (e.g., photolysis) to: (i) determine the rate and extent of steroid transformation, (ii) isolate and identify products that are formed, and (iii) evaluate products or product mixtures for biological activity. These experimental results can be used to help guide occurrence studies for any products of concern in the environment and also guide computational predictions or rationalizations of chemical reactivity. Ultimately, the goal is to expand upon our awareness and understanding of how these potent endocrine ligands behave in the environment and how they potentially affect ecosystem health.

Chapter 2 discusses the reaction of glucocorticoids (GC)s with aqueous chlorine (effectively, HOCl) to simulate their fate during engineered drinking water and wastewater chemical disinfection. Numerous transformation pathways were unveiled, including interconversion of GCs (e.g., endogenous cortisol to synthetic prednisolone), production of known androgens in the adrenosterone class, and chlorination of GCs (e.g., formation of 9-chloro-prednisone). We also showed that other advanced processes (e.g., oxidation via ozonation) result in more complete degradation of such pollutants, and may be better alternatives to chemical disinfection at eliminating bioactive steroidal product formation.

In Chapter 3, results of the direct photolysis of dienogest (DNG), a widely prescribed oral contraceptive agent, are presented to simulate its fate in natural sunlit surface waters and engineered photochemical treatment systems (e.g., UV disinfection systems). The major products (~ 80% of the converted mass in neutral aqueous solutions) were identified to be photohydrates resulting from photochemical-induced incorporation of water into parent DNG. These products were found to be prone to dehydration in the dark, and thus, a source of substantial DNG regeneration (~ 65% after 72 h in neutral solutions). Other minor, non-revertible products were also identified, including two known estrogens. Although minor in initial yield, these estrogens are likely to accumulate over time through repeated cycling between DNG and its photohydrates, and thus, dominate DNG long-term fate.

It was also found that DNG undergoes an unusual photochemical rearrangement to produce a minor product with a novel tetracyclic ring system--the subject of Chapter 4. Further, the generality of this unique photorearrangement process was explored through extension to the photolysis of two other dienone pharmaceutical steroids (e.g., the androgens methyldienolone and dienedione). Surprisingly, despite the significant change in core steroidal structure, the rearrangement products retain some progesterone receptor (PR) and androgen receptor (AR) bioactivity (i.e., low-µM to sub-nm EC50 values). Again, these represent other non-revertible, minor products that are likely to accumulate over time, with likely adverse ecological consequences.

Chapter 5 covers results arising from the direct photolysis of trenbolone acetate (TBA) metabolites in the presence of model nucleophiles (e.g., sodium azide, sodium thiosulfate, ammonium hydroxide, hydroxylamine, and humic acid), some of which would be expected to be present, along with TBA metabolites, in agriculturally-impacted water resources. Previous studies by our group revealed that TBA metabolites undergo photohydration-thermal dehydration cycling, like that described above for DNG photolysis. The objective of this study was to determine if other nucleophiles would outcompete water for photochemical incorporation across the TBA metabolite extended conjugation system. It was found that TBA metabolite photolysis results in photochemical (and at times thermal) addition of the nucleophile to the TBA metabolites. It was also found that the addition products undergo thermal elimination in the dark and contribute to TBA metabolite regeneration, and therefore, are expected to increase TBA metabolite persistence in water resources.

Finally, Chapter 6 discusses the reactions of various trienone and dienone steroids with aqueous chlorine to simulate their fate during engineered drinking water and wastewater chemical disinfection. Single-step transformation pathways were unveiled for each steroid class, including 4-chlorination (trienones) and 9,10-epoxidation (dienones). Chlorination at position C-4 is known to enhance anabolic potency of androgenic steroids and the 9,10-epoxy products were found to undergo acid- or base-catalyzed ring-opening and aromatization to yield known estrogenic products. In addition, Chapter 7 provides conclusions and future directions, while Chapter 8 details the experimental methods and procedures used throughout this thesis.

Collectively, the results presented herein confirm our overall hypothesis that steroid transformation products would be expected to contribute to residual biological activity often detected in water resources. Furthermore, the results indicate that the transformation of high potency pharmaceuticals does not automatically equate with reduction or elimination of hazards to exposed organisms, especially in cases where such compounds have potential to form products exhibiting diverse biological endpoints. More holistic approaches to risk assessment of such high potency environmental contaminants are needed in order to accurately assess the fate and effects of such emerging pollutant classes and their bioactive transformation products.

Keywords

Bioactive transformation products, Chlorination, Emerging pollutant classes, Environmental transformations, Photolysis, Steroids

Pages

xxiv, 258 pages

Bibliography

Includes bibliographical references (pages 246-258).

Comments

This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: http://www.lib.uiowa.edu/sc/contact/

Copyright

Copyright © 2017 Nicholas Craig Pflug

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