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The mammalian circadian system is resistant to dioxin.

ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that is bound and activated by many toxic ubiquitous environmental contaminants, including the halogenated aromatic hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The AhR belongs to a family of proteins that contain basic helix-loop-helix/Per-ARNT-SIM (bHLH/PAS) domains. The circadian clock protein, BMAL1, is also a bHLH-PAS transcription factor and has been shown to interact with the AhR. AhRs are expressed in nearly every mammalian tissue, including the suprachiasmatic nuclei (SCN), and previous studies have suggested that activation of the AhR with dioxins affects rhythmicity in circadian clocks. In this study, the authors tested the hypothesis that activation of the aryl hydrocarbon receptor with the potent dioxin, TCDD, alters the organization of the mammalian circadian system by measuring bioluminescence from tissues explanted from PER2::LUCIFERASE mice. They found that in vitro treatment of explanted tissues with TCDD did not alter the periods, amplitudes, or damping rates of the PER2::LUC rhythms compared with controls. Likewise, in vivo treatment with TCDD had no effect on the phase relationship between central and peripheral oscillators. Together, these data demonstrate that activation of the AhR with TCDD does not directly or systemically alter the mouse circadian system.

SUBMITTER: Pendergast JS

PROVIDER: S-EPMC3337685 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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The mammalian circadian system is resistant to dioxin.

Pendergast Julie S JS Yamazaki Shin S

Journal of biological rhythms 20120401 2

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that is bound and activated by many toxic ubiquitous environmental contaminants, including the halogenated aromatic hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The AhR belongs to a family of proteins that contain basic helix-loop-helix/Per-ARNT-SIM (bHLH/PAS) domains. The circadian clock protein, BMAL1, is also a bHLH-PAS transcription factor and has been shown to interact with the AhR. AhRs are expressed ...[more]

PMID: 22476776

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Project description:The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD50 of >9600 µg/kg for H/W rats is higher than for any other wild-type mammal known. We have previously shown that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion, H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100 µg/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. . A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L-E than H/W rats. At ten days almost all expressed genes were dysregulated in L-E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome. Rats from sensitive (Long-Evans, LE) and resistant (Han/Wistar, HW) strains were treated with 100 ug/kg TCDD or corn oil vehicle and sacrificed either 4 or 10 days after treatment. LE control rats were either fed normally or feed-restricted to control for the wasting effects of TCDD treatment. Each treatment group contains four or five animals (biological replicates), each of which was assayed on an individual microarray.

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The mammalian circadian system is resistant to dioxin.

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The mammalian circadian system is resistant to dioxin.

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