Role of Aryl Hydrocarbon Receptor in Circadian Rhythm: A Novel Pathway to Dioxin Toxicity

For decades, the study of aryl hydrocarbon receptor (AhR), a transcription factor and a member of the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) domain family, has been focused on its role in mediating adverse effects of some environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). However, a physiological role of AhR remains unknown. Many members of PAS domain family play a role in regulation of circadian rhythm; therefore the role of AhR in the circadian rhythm was investigated. First, to examine AhR as a basic component of the molecular clockwork, the circadian mRNA expression of AhR and its signaling targets in the suprachiasmatic nucleus (SCN), the master clock, and in the liver, a peripheral clock, were determined in mice. The circadian phenotype was also characterized in mice lacking AhR. Although not robust as some of the well-characterized clock genes, diurnal variation was observed in both tissues under light/darkness and constant darkness conditions. Second, the role of tryptophan (TRP) photoproducts that act as AhR agonists, were assessed in the light-regulation of circadian rhythm. Both exposure to light or treatment with TRP photoproducts activated AhR signaling in vitro and in vivo. Glutamate-induced phase shifting was inhibited by preincubation with FICZ in in vitro SCN slice cultures. Lastly, potential effects of TCDD on circadian rhythm were examined at the molecular and behavioral level. Exposure to TCDD affected circadian expression of clock genes and attenuated the light-induced phase shifts. Taken together, these results suggest that the AhR is potentially involved in regulating the molecular clockwork, especially in the light-regulatory pathway of circadian rhythm; exposure to environmental contaminants that interact with AhR may affect the ability of humans and animals to adjust their circadian rhythm to the external environment. Although further studies are necessary to decipher mechanisms of how AhR plays a role in circadian rhythm, this work opens new perspectives in both dioxin toxicology and chronobiology.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Mukai, Motoko

Contributors dc:contributor

• Tischkau, Shelley A.
• Cooke, Paul S.

• Biology, Physiology

Language dc:language

eng

Identifier

(MiAaPQ)AAI3250296

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/87939