Circadian clock disruption in the mouse ovary in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Dec 25, 2010Toxicology letters

Disruption of the mouse ovary's daily biological clock by a toxic chemical

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Abstract

A single 1 μg/kg dose of TCDD alters the expression of the canonical clock genes Bmal1 and Per2 in the ovaries of adult female C57BL/6J mice.

TCDD exposure compromises ovarian function by affecting follicle maturation and steroid synthesis.
AhR and its binding partner, ARNT, are typically associated with the toxic effects of dioxins, but recent evidence suggests additional signaling interactions.
The circadian clock gene expression in the ovary is disrupted after TCDD treatment.
AhR expression displays a circadian pattern in control ovaries, which is altered following TCDD exposure.
Co-localization of AhR with BMAL1 was observed in various ovarian cell types, indicating a potential interaction.
Interactions between AhR and BMAL1 are influenced by the time of day and are enhanced after TCDD exposure.

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Activation of the aryl hydrocarbon receptor (AhR) by the highly toxic, prototypical ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or other dioxin-like compounds compromises ovarian function by altering follicle maturation and steroid synthesis. Although alteration of transcription after nuclear translocation and heterodimerization of AhR with its binding partner, aryl hydrocarbon nuclear transporter (ARNT), is often cited as a primary mechanism for mediating the toxic effects of dioxins, recent evidence indicates that crosstalk between AhR and several other signaling pathways also occurs. Like the circadian clock genes, AhR is a member of the basic helix-loop-helix, Per-ARNT-SIM (bHLH-PAS) domain family of proteins. Thus, these studies tested the hypothesis that TCDD can act to alter circadian clock regulation in the ovary. Adult female c57bl6/J mice entrained to a typical 12h light/12h dark cycle were exposed to a single 1 μg/kg dose of TCDD by gavage. Six days after exposure, animals were released into constant darkness and ovaries were collected every 4h over a 24h period. Quantitative real-time PCR and immunoblot analysis demonstrated that TCDD exposure alters expression of the canonical clock genes, Bmal1 and Per2 in the ovary. AhR transcript and protein, which displayed a circadian pattern of expression in the ovaries of control mice, were also altered after TCDD treatment. Immunohistochemistry studies revealed co-localization of AhR with BMAL1 in various ovarian cell types. Furthermore, co-immunoprecipitation demonstrated time-of-day dependent interactions of AhR with BMAL1 that were enhanced after TCDD treatment. Collectively these studies suggest that crosstalk between classical AhR signaling and the molecular circadian clockworks may be responsible for altered ovarian function after TCDD exposure.

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Circadian clock disruption in the mouse ovary in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin

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