All ETDs from UAB

Advisory Committee Chair

Daniel A Gorelick

Advisory Committee Members

Chenbei Chang

Farah Lubin

Lori L McMahon

Talene Yacoubian

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In a society driven by technology and industry, we must be increasingly aware of how changes to our environment impact our health. This is especially true concerning embryonic development, which is easily influenced by extra-embryonic factors, including environmental contaminants. Determining how exogenous compounds are absorbed, which receptors they act through, and how these receptors act endogenously is important to fully understand to what extent developmental exposures impact fetal and adult health. I have used the zebrafish model system to address these questions for two classes of environmentally-relevant chemicals—estrogens and dioxins. First, I developed an assay to measure the uptake of exogenous chemicals into zebrafish embryos using radiolabeled estradiol. I found that uptake increases with increasing exposure duration, concentration, and developmental stage. A small percentage (<4%) of estradiol was absorbed by embryos, suggesting that supraphysiologic concentrations are required to achieve physiologically relevant levels in vivo. I expanded this assay to two structurally-distinct estrogens, bisphenol A (BPA) and ethinyl-estradiol (EE2). I found that while EE2 uptake was similar to estradiol, BPA uptake was significantly decreased compared to estradiol. This suggests that compound structure determines uptake. Next, I studied the function of an important environmental sensor, the aryl hydrocarbon receptor (AHR), in zebrafish. Zebrafish have three paralogues of the human AHR (ahr1a, ahr1b, ahr2), therefore it was necessary to determine to what extent each paralogue is functionally analogous to the human AHR. To answer this question, I studied the impact of generating loss-of-function mutations in each paralogue on embryonic and adult development, including a novel ahr1a;ahr1b double mutant. I found that ahr2, but not ahr1a or ahr1b, is required for dioxin toxicity. Further, although zebrafish with mutations in Ah receptors were morphologically normal during larval development, ahr2, but not ahr1, mutants demonstrated defects in fin and craniofacial morphology in adulthood. Future studies should focus on ahr2 as the primary functional AHR in zebrafish. Together, these results describe the absorption and function of environmentally-relevant compounds and receptors in zebrafish, strengthening the use of zebrafish as a clinically-relevant model to test the impact of environmental compounds on human development and maturation.

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