Date of Award

Spring 5-5-2023

Document Type

Thesis

Degree Name

Bachelor of Arts

Department

Biochemistry & Molecular Biology

First Advisor

Wade Powell

Abstract

The AHR is a ligand-activated transcription factor that mediates the toxic effects of chlorinated dioxins such as TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin). Since its discovery, a vast literature has addressed the molecular and organismal response to TCDD and other AHR agonists. However, far less work has investigated AHR antagonists, especially on species-specific differences in their relative potencies. Unlike agonists, antagonist ligands bind to the AHR, but do not elicit the characteristic responses, including cyp1a induction. In mixtures, antagonists can compete with agonists for interaction with AHR’s ligand binding cavity and attenuate the response to agonists. A recent study identified folic acid and vitamin B12 as antagonists of the human AHR in vitro. Antagonism by these vitamins may have a mechanistic role in the competitive inhibition of TCDD-induced cyp1a1 expression in HepG2 cells (D. J. Kim et al., 2020). Our lab previously demonstrated that AHRs of the African Clawed frog, Xenopus laevis, have low binding affinity for TCDD (Lavine et al., 2005). We hypothesized that because of the low AHR binding affinity to TCDD, the frog AHRs may exhibit a similar low-affinity for antagonists. In this study, we found that folic acid did not act as a potent antagonist of Xenopus laevis AHRs, since it does not attenuate TCDD-induced cyp1a6 expression. With this finding, we highlight species-specific differences in the relative potencies of AHR antagonists. Like TCDD, antagonists may bind the frog AHRs with relatively low affinity, limiting their potency. We suggest that this potential fundamental role of the AHR differs between mammals and amphibians, and that the commonly used Xenopus developmental toxicity screenings (including FETAX and amphibian metamorphosis screenings) represent a complex model of the human response to these compounds.

Rights Statement

All rights reserved. This copy is provided to the Kenyon Community solely for individual academic use. For any other use, please contact the copyright holder for permission.

Download

Share

COinS