Disruption of period gene expression alters the inductive effects of dioxin on the AhR signaling pathway in the mouse liver

Nov 29, 2008Toxicology and applied pharmacology

Changes in the body clock gene affect how dioxin influences the toxin response system in mouse liver

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Abstract

Targeted disruption of Per1 in mice resulted in a 2-fold greater induction of Cyp1A1 expression following exposure to TCDD.

The aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) are involved in drug and toxin metabolism in the liver.
Targeted disruption or siRNA inhibition of Per1 and Per2 influences the regulation of the AhR signaling pathway.
Treatment with TCDD induced Cyp1A1 and Cyp1B1 expression in mouse liver across all genotypes.
Inhibition of Per1 led to increased TCDD-induced expression of Cyp1A1 and Cyp1B1 in liver cells.
In contrast, siRNA inhibition of Per2 resulted in decreased expression of these genes and the AhR pathway in response to TCDD.

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The aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) are transcription factors that express Per-Arnt-Sim (PAS) DNA-binding motifs and mediate the metabolism of drugs and environmental toxins in the liver. Because these transcription factors interact with other PAS genes in molecular feedback loops forming the mammalian circadian clockworks, we determined whether targeted disruption or siRNA inhibition of Per1 and Per2 expression alters toxin-mediated regulation of the AhR signaling pathway in the mouse liver and Hepa1c1c7 hepatoma cells in vitro. Treatment with the prototypical Ahr ligand, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), had inductive effects on the primary targets of AhR signaling, Cyp1A1 and Cyp1B1, in the liver of all animals, but genotype-based differences were evident such that the toxin-mediated induction of Cyp1A1 expression was significantly greater (2-fold) in mice with targeted disruption of Per1 (Per1(ldc) and Per1(ldc)/Per2(ldc)). In vitro experiments yielded similar results demonstrating that siRNA inhibition of Per1 significantly increases the TCDD-induced expression of Cyp1A1 and Cyp1B1 in Hepa1c1c7 cells. Per2 inhibition in siRNA-infected Hepa1c1c7 cells had the opposite effect and significantly decreased both the induction of these p450 genes as well as AhR and Arnt expression in response to TCDD treatment. These findings suggest that Per1 may play a distinctive role in modulating AhR-regulated responses to TCDD in the liver.

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Disruption of period gene expression alters the inductive effects of dioxin on the AhR signaling pathway in the mouse liver

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