Disruption of Clock Gene Expression Alters Responses of the Aryl Hydrocarbon Receptor Signaling Pathway in the Mouse Mammary Gland

Abstract

The biological effects of many environmental toxins are mediated by genes containing Per-Arnt-Sim (PAS) domains, the aryl hydrocarbon receptor (AhR), and AhR nuclear translocator. Because these transcription factors interact with other PAS genes that form the circadian clockworks in mammals, we determined whether targeted disruption of the clock genes, Per1 and/or Per2, alters toxin-induced expression of known biological markers in the AhR signaling pathway. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a prototypical Ahr agonist, had an inductive effect on mammary gland expression of cytochrome P450, subfamily I, polypeptide 1 (Cyp1A1) mRNA regardless of genotype. However, TCDD-mediated Cyp1A1 induction in the mammary glands of Per1 ldc and Per1 ldc /Per2 ldc mice was significantly (17.9-and 5.9-fold) greater than that in wild-type (WT) animals. In addition, TCDD-induced Cyp1B1 expression in Per1ldc and Per1 ldc /Per2 ldc mammary glands was significantly increased relative to that in WT mice. Similar to in vivo observations, experiments using primary cultures of mammary gland tissue demonstrated that TCDD-induced Cyp1A1 and Cyp1B1 expression in Per1 ldc and Per1 ldc /Per2 ldc mutant cells was significantly greater than that in WT cultures. AhR mRNA levels were distinctively elevated in cells derived from all mutant genotypes, but they were commonly decreased in WT and mutant cultures after TCDD treatment. In WT mice, an interesting corollary is that the inductive effects of TCDD on mammary gland expression of Cyp1A1 and Cyp1B1 vary over time and are significantly greater during the night. These findings suggest that clock genes, especially Per1, may be involved in TCDD activation of AhR signaling pathways.

Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-α Pathway Activity in Mice

“…Disruption of Per1 and Per2 alters AhR (Qu et al 2007). AhR activation changes the expression of liver Per1 and BMAL1.…”

“…Chronic AhR activation also inhibits the responsiveness of the circadian clock to changes in environmental lighting (Mukai et al 2008). Conversely, disruption of Per1 and Per2 expression alters the AhR signaling pathway (Qu et al 2007, 2010). Collectively, the data reveal a complex relationship between AhR signaling and clock genes.…”

Behavioral Rhythmicity of Mice Lacking AhR and Attenuation of Light-Induced Phase Shift by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

“…Interrelationships between AhR signaling and the Per genes have been demonstrated; TCDD-induced AhR signaling is altered in the mammary glands of Per1 ldc and Per1 ldc /Per2 ldc (Qu et al 2007). The physiological significance of these interactions requires further investigation.…”

p-Anilinoaniline Enhancement of Dioxin-Induced CYP1A1 Transcription and Aryl Hydrocarbon Receptor Occupancy of CYP1A1 Promoter: Role of the Cell Cycle

“…The first entails the cell cycle and the second circadian rhythms. Regarding the latter, TCDD-mediated induction of CYP1A1 in the liver and mammary glands of mice is 23-to 40-fold greater at night than during daytime (Qu et al, 2007(Qu et al, , 2010. This diurnal rhythm in CYP1A1 responsiveness to TCDD is inversely related to the expression of the protein Period 1 (Metz et al, 2006: Qu et al, 2010, a key protein regulator of the circadian clock (Reppert and Weaver, 2002).…”