Female Sprague–Dawley Rats Exposed to a Single Oral Dose of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Exhibit Sustained Depletion of Aryl Hydrocarbon Receptor Protein in Liver, Spleen, Thymus, and Lung

Pollenz, Richard S.; Santostefano, Michael J.; Klett, Eric L.; Richardson, Vicki M.; Necela, Brian M.; Birnbaum, Linda S.

doi:10.1006/toxs.1998.2439

Cited by 40 publications

(32 citation statements)

References 13 publications

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“…These data are supported by results obtained from other laboratories as well [35]. This might indicate that some individuals are more sensitive than others to the effects of dioxin.…”

Section: Discussionsupporting

confidence: 88%

“…The AhR and ARNT are quite ubiquitous in that their mRNA and protein have been identified in most tissues analyzed [19,30,32,34,35], therefore it seems evident that TCDD has the potential to exert its effects at many loci. Although Kainu et al [5] were not able to localize either AhR or ARNT mRNA to the hypothalamus o r t h e b r a i n s t e m o f t h e r a t u s i n g i n -s i t u hybridization, AhR mRNA has been identified in the hypothalamus by slot-blot hybridization [6].…”

Section: Discussionmentioning

confidence: 99%

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Short-Term Hormone Release from Adult Female Rat Hypothalamic and Pituitary Explants is not Altered by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Trewin

Woller

Wimpee

et al. 2007

Journal of Reproduction and Development

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Abstract. 2, 3, 7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has adverse effects on reproduction, in part due to direct actions at the ovary. It is unclear whether effects are further mediated by glands that regulate ovarian function. We investigated whether effects of TCDD are mediated via the hypothalamic-pituitary axis. Hypothalamic and pituitary tissues were cultured in medium with and without TCDD. TCDD did not alter GnRH release from hypothalamic samples. It continued to be pulsatile with no differences in the average peak frequency, average peak amplitude, or baseline GnRH release. TCDD did not alter GnRH-induced release of gonadotropins from pituitary samples. There were no differences in average peak amplitude or baseline release. AhR, ARNT or ERα mRNA copy numbers in cultured pituitaries were not affected by TCDD. Our data suggest that TCDD effects on ovarian function are not mediated through the hypothalamic or pituitary release parameters tested in this study.

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“…These data are supported by results obtained from other laboratories as well [35]. This might indicate that some individuals are more sensitive than others to the effects of dioxin.…”

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Short-Term Hormone Release from Adult Female Rat Hypothalamic and Pituitary Explants is not Altered by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Trewin

Woller

Wimpee

et al. 2007

Journal of Reproduction and Development

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“…In vivo studies, however, have failed to consistently demonstrate a prominent physiologic effect caused AHR by ligand binding. In Sprague Dawley rats, a single oral dose of 10 or 50 µg/kg produced a pronounced initial reduction of liver and cytosol AHR concentrations, though, in the case of the former, depletion persisted for 14 days, while in the latter, depletion was followed by AHR induction (Pollenz et al, 1998;Franc et al, 2001a). A similar effect was also reported for Hans/Wistar rats, though these rats had lower liver AHR concentrations than either SD or L-E rats regardless of TCDD treatment (Franc et al, 2001a).…”

Section: Principles Of Tcdd Sensitivitymentioning

confidence: 99%

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

et al. 2005

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ᮀTCDD and other polyhalogenated aromatic hydrocarbon ligands of the aryl hydrocarbon receptor (AHR) have been classically considered as non-genotoxic compounds because they fail to be directly mutagenic in either bacteria or most in vitro assay systems. They do so in spite of having repeatedly been linked to oxidative stress and to mutagenic and carcinogenic outcomes. Oxidative stress, on the other hand, has been used as a marker for the toxicity of dioxin and its congeners. We have focused this review on the connection between oxidative stress induction and the toxic effects of fetal and adult dioxin exposure, with emphasis on the large species difference in sensitivity to this agent. We examine the roles that the dioxin-inducible cytochromes P450s play in the cellular and toxicological consequences of dioxin exposure with emphasis on oxidative stress involvement. Many components of the health consequences resulting from dioxin exposure may be attributable to epigenetic mechanisms arising from prolonged reactive oxygen generation.

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“…Since the concentration of an endogenous signaling protein will ultimately determine the responsiveness of the cell to a given signal, there has been interest in understanding how modulation of AHR protein levels impact normal cellular functions as well as the biological responses to TCDD [reviewed in 5,6 ]. For example, studies have shown that reductions in the level of AHR protein in culture can impact the magnitude of AHR-mediated induction of CYP1A1 and affect cell growth rates [ 7,8 ]. Conversely, it has been reported that a constitutively active AHR expressed in transgenic mice causes a myriad of effects including reduced life span and stomach tumors [ 9,10 ].…”

Section: Introductionmentioning

confidence: 99%

Specific blockage of ligand-induced degradation of the Ah receptor by proteasome but not calpain inhibitors in cell culture lines from different species

Pollenz

2007

Biochemical Pharmacology

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To firmly establish the pathway involved in ligand-induced degradation of the AHR, cell lines derived from mouse rat or human tissues were exposed to inhibitors specific to the proteasome or calpain proteases and exposed to TCDD. The level of endogenous AHR and CYP1A1 protein was then evaluated by quantitative Western blotting. Treatment of cells with the calpain inhibitors: calpeptin, calpain inhibitor III, or PD150606 either individually or in combinations up to 75μM did not reduce TCDD-induced degradation of the AHR, the induction of endogenous CYP1A1 or the nuclear accumulation of the AHR. The activity of the inhibitors was verified with an in vivo calpain assay. In contrast, exposure of cells to the specific proteasome inhibitors: epoxomicin (1-5μM), proteasome inhibitor I (5-10μM) or lactacystin (5-15μM) completely inhibited TCDD-induced degradation of the AHR. Inhibition of AHR degradation with these compounds did not reduce the induction of endogenous CYP1A1. In addition, exposure of the Hepa-1 line to the various proteasome inhibitors caused an accumulation of the AHR in the nucleus in the absence of TCDD exposure. Finally, Western blot analysis of the DNA bound AHR showed that its molecular mass was unchanged in comparison to the unliganded (cytoplasmic) AHR. Thus, these studies conclusively implicate the proteasome and not calpain proteases in the ligand-induced degradation of the mouse, rat and human AHR and suggest that the pharmacological use of proteasome inhibitors may impact the time course and magnitude of gene regulatory events mediated through the AHR.

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Female Sprague–Dawley Rats Exposed to a Single Oral Dose of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Exhibit Sustained Depletion of Aryl Hydrocarbon Receptor Protein in Liver, Spleen, Thymus, and Lung

Cited by 40 publications

References 13 publications

Short-Term Hormone Release from Adult Female Rat Hypothalamic and Pituitary Explants is not Altered by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Short-Term Hormone Release from Adult Female Rat Hypothalamic and Pituitary Explants is not Altered by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

Specific blockage of ligand-induced degradation of the Ah receptor by proteasome but not calpain inhibitors in cell culture lines from different species

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