| The aryl hydrocarbon receptor (Ah receptor or AHR) is a ligand-activated transcription factor that mediates expression of genes involved in metabolism of xenobiotics like dioxin and initiation of key developmental signals during vertebrate embryogenesis. A large volume of AHR research has elucidated the molecular mechanisms of ligand activation, co-factor heterodimerization, DNA binding, and initiation of transcription. However, despite over 30 years of research, there are two major questions that remain unanswered: (1) What are the mechanisms leading to dioxin toxicity?, and (2) What is the adaptive role of AHR in protecting against disease-related conditions? The former question addresses the toxic AHR response pathway—a pathway that involves downstream events (genomic or non-genomic) of AHR activation that lead to deleterious effects. In contrast, the latter question addresses the adaptive AHR response pathway—a pathway that involves AHR-dependent upregulation of metabolic enzymes that protect against adverse pathologic effects. Therefore, the aims of this dissertation were to better understand these distinct AHR signaling pathways, as well as better define the relationships between these pathways and toxic injury at the tissue and organ levels of organization.;The small teleost fish, Japanese medaka (Oryzias latipes), was used as an animal model for two fundamental reasons: (1) Very little is known regarding AHR biology in this important toxicological animal model, and (2) Publically available genomic information for medaka enables mapping and analysis of AHR-responsive genes, including cis-regulatory elements. To address questions related to the toxic response pathway initiated by dioxin, the first set of studies employed gene expression profiling- and bioinformatic-based strategies to demonstrate that (1) transcriptional events are highly organ-specific and are positively correlated with pathologic alterations, (2) AHR-dependent and AHR-independent gene expression precedes toxic effects in the liver, and (3) dioxin toxicity appears to be independent of CYP1A induction. To address questions related to the adaptive response pathway, the second set of studies focused on modeling bile stasis (a condition resulting in elevated levels of hepatic bile) in medaka to demonstrate that (1) transient AHR activation and CYP1A induction occurs during hepatobiliary impairment, (2) pre-treatment with an AHR agonist partially protects against acute biliary dysfunction, and (3) the bile pigment bilirubin activates AHR-dependent, AHRE-driven transcription in mouse hepatoma cells, suggesting that bile pigments may be AHR agonists during bile stasis. |
