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Author ORCID Identifier

https://orcid.org/0000-0001-6927-2803

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Public Health

Year Degree Awarded

2021

Month Degree Awarded

September

First Advisor

Alicia R. Timme-Laragy

Second Advisor

Laura N. Vandenberg

Third Advisor

Alexander Suvorov

Fourth Advisor

Yeonhwa Park

Subject Categories

Animals | Developmental Biology | Disorders of Environmental Origin | Endocrinology, Diabetes, and Metabolism | Environmental Health | Environmental Public Health | Hepatology | Maternal and Child Health | Toxicology

Abstract

The environmental pollutant 3,3’-dichlorobiphenyl (PCB-11) is a lower-chlorinated polychlorinated biphenyl (PCB) congener present in air and water samples. Both PCB-11 and its metabolite, 4-PCB-11-Sulfate, are detected in humans, including in pregnant women. The work conducted for this dissertation takes a developmental toxicology approach and uses zebrafish (Danio rerio) to investigate PCB-11’s potential impacts to the liver and pancreas. Chapter 1 introduces PCBs and the current knowledge gaps. Chapter 2 investigates PCB-11 interactions in short-term 4-day exposures with the Aryl hydrocarbon receptor (Ahr) pathway in both 0-20 mM individual and mixture exposures with other Ahr agonists. In Chapter 3, PCB-11 metabolites 4-OH-PCB-11 and 4-PCB-11-Sulfate are assessed in both 4-day and in longer-term 15-day chronic exposures. Finally in Chapter 4, the role of Nrf2, a master regulator of oxidative stress, is explored in the context of these short and long-term exposure settings. Throughout these chapters, in vivo ethoxyresorufin-O-deethylase (EROD) bioassay, RT-qPCR, RNAseq, Oil-Red-O (ORO) staining, fatty acid profiling, and fluorescence microscopy techniques, as well as the use of Tg(ins:GFP) and Tg(gut:GFP) transgenic and nrf2afh318/fh318 mutant zebrafish, were used to assess toxicity. The results from this work indicate that PCB-11 is a mild Ahr agonist, but in co-exposures can inhibit either the Ahr or downstream Cyp1a enzyme activity depending on the co-exposure, resulting in different toxicity outcomes. 4-PCB-11-Sulfate can also inhibit Cyp1a activity but does not interfere with the toxicity outcomes of co-exposures, however, chronic 15-day exposure to 4-PCB-11-Sulfate increases hepatic neutral lipids 30%, increases pancreatic β-cell cluster area in the primary Islet of Langerhans 8%, and leads to better survival at 80-85% compared to 63-75% for unexposed fish. Nrf2a seems to play a minor role in the Cyp1a enzyme inhibition and phenotypic effects observed with PCB-11 and 4-PCB-11-Sulfate 4-day exposures but plays an important role in development as well as for DHA production in the presence of 4-PCB-11-Sulfate. Chapter 5 discusses the findings from Chapters 2-4. The data presented contributes to the understanding of this sub-class of PCB compounds and provides insight into how PCB-11 could potentially impact human health.

DOI

https://doi.org/10.7275/23395700

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

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