The clock genes period 1 and period 2 mediate diurnal rhythms in dioxin-induced Cyp1A1 expression in the mouse mammary gland and liver

Transcription factors expressing Per-Arnt-Sim (PAS) domains are key components of the mammalian circadian clockworks found in most cells and tissues. Because these transcription factors interact with other PAS genes mediating xenobiotic metabolism and because toxin responses are often marked by daily variation, we determined whether the toxin-mediated activation of the signaling pathway involving several PAS genes, the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT), fluctuates rhythmically and whether this diurnal oscillation is affected by targeted disruption of key PAS genes in the circadian clockworks, Period 1 (Per1) and Per2. Treatment with the prototypical Ahr ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), had inductive effects on a key target of AhR signaling, Cyp1A1, in both the mammary gland and liver of all animals. In wild type mice, the amplitude of this TCDD-induced Cyp1A1 expression in the mammary gland and liver was significantly greater (23–43-fold) during the night than during the daytime. However, the diurnal variation in the TCDD induction of mammary gland and liver Cyp1A1 expression was abolished in Per1ldc, Per2ldc and Per1ldc/Per2ldc mutant mice, suggesting that Per1, Per2 and their timekeeping function in the circadian clockworks mediate the diurnal modulation of AhR-regulated responses to TCDD in the mammary gland and liver.