Role of the AHR and its Structure in TCDD Toxicity

Pohjanvirta, Raimo; Korkalainen, Merja; Moffat, Ivy D.; Boutros, Paul C.; Okey, Allan B.

doi:10.1002/9781118140574.ch12

Cited by 19 publications

(23 citation statements)

References 152 publications

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“…and testis lesions, hypoglycaemia, and elevated plasma FFA levels (all type II effects) (Pohjanvirta, et al 2011, Viluksela, et al 1999. Hence, these novel AHR activators bring about only a subset of the response spectrum previously reported to TCDD, and all those effects belong to type I category.…”

Section: Accepted Manuscriptmentioning

confidence: 87%

“…retinoids (Lampen, et al 2000, Shmarakov 2015, steroid hormones (Spink, et al 1992) and, apparently, polyunsaturated fatty acids (Hankinson 2016). Further, unlike previously presumed, Cyp1a1 induction does not automatically indicate dioxin-like toxicity (Hu, et al 2007, Pohjanvirta, et al 2011.…”

Section: Accepted Manuscriptmentioning

confidence: 93%

“…All of the effects mentioned above are classified as type I, and are thus responses that are similar in both TCDD-sensitive L-E and TCDD-resistant H/W rat strains (Pohjanvirta, et al 2011). In this rat strain model of TCDD toxicity, TCDD resistance is based on an altered transactivation domain structure in the AHR of the resistant H/W strain.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

Mahiout

Lindén

Esteban

et al. 2017

Toxicology and Applied Pharmacology

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The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75-92.5mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100mg/kg/day; and IMA-07101: 75mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro, the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators.

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Section: Accepted Manuscriptmentioning

confidence: 87%

Section: Accepted Manuscriptmentioning

confidence: 93%

Section: Accepted Manuscriptmentioning

confidence: 99%

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Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

Mahiout

Lindén

Esteban

et al. 2017

Toxicology and Applied Pharmacology

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“…These chemically heterogeneous compounds, generally represented in toxicity studies by the most potent member 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), share a common fundamental mechanism of action, conveying their effects through an intracellular aryl hydrocarbon receptor (AHR) [6]. Furthermore, structural variation in the AHR appears to be the major determinant of the astonishingly wide intra- and inter-species differences in susceptibility to dioxin toxicity [7].…”

Section: Introductionmentioning

confidence: 99%

Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Hormones of Energy Balance in a TCDD-Sensitive and a TCDD-Resistant Rat Strain

Lindén

Lensu

Pohjanvirta

2014

IJMS

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One of the hallmarks of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a drastically reduced feed intake by an unknown mechanism. To further elucidate this wasting syndrome, we followed the effects of a single large dose (100 μg/kg) of TCDD on the serum levels of several energy balance-influencing hormones, clinical chemistry variables, and hepatic aryl hydrocarbon receptor (AHR) expression in two rat strains that differ widely in their TCDD sensitivities, for up to 10 days. TCDD affected most of the analytes in sensitive Long-Evans rats, while there were few alterations in the resistant Han/Wistar strain. However, analyses of feed-restricted unexposed Long-Evans rats indicated several of the perturbations to be secondary to energy deficiency. Notable increases in ghrelin and glucagon occurred in TCDD-treated Long-Evans rats alone, which links these hormones to the wasting syndrome. The newly found energy balance regulators, insulin-like growth factor 1 and fibroblast growth factor 21 (FGF-21), appeared to function in concert in body weight loss-induced metabolic state, and FGF-21 was putatively linked to increased lipolysis induced by TCDD. Finally, we demonstrate a reverse set of changes in the AHR protein and mRNA response to TCDD and feed restriction, suggesting that AHR might function also as a physiological regulator, possibly involved in the maintenance of energy balance.

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“…Most of the toxic effects of dioxins and related compounds are mediated by aryl hydrocarbon receptor (AhR) [5,6], and the molecular basis for wide interand intraspecies differences seems to be related to polymorphisms in this receptor [7]. Activation of the AhR leads to induction or repression of a varied combination of genes, including cytochrome P450 1A1 (CYP1A1), the most studied gene for AhR activation.…”

Section: Introductionmentioning

confidence: 99%

Significant interspecies differences in induction profiles of hepatic CYP enzymes by TCDD in bank and field voles

Murtomaa-Hautala

Korkalainen

Pelkonen

et al. 2012

Enviro Toxic and Chemistry

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The gene expression and induction of cytochrome P450 (CYP)-enzymes following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) peroral administration was studied in the livers of two wild vole species--the bank vole (Myodes glareolus) and the field vole (Microtus agrestis). The dioxin-sensitive C57BL/6 mouse was used as a reference. Doses of 0.05, 0.5, 5.0, and 50 µg/kg were applied to ascertain a dose-response relationship, and the dose of 50 µg/kg was applied to the study time course for up to 96 h. The cytochrome P450 1A1 (CYP1A1) mRNA expression showed an expected dose-dependent increase equally in both vole species. Bank voles expressed notably higher CYP2A mRNA levels as compared with field voles. Both species exhibited dose-dependent increases in putative CYP1A-, CYP2B-, and CYP2A-associated activities as measured by fluorometric assays for ethoxyresorufin-O-deethylase (EROD), penthoxyresorufin-O-depenthylase (PROD), and 7-ethoxycoumarin-O-deethylase (ECOD), respectively. Putative CYP2A-associated coumarin-7-hydroxylase (COH) activity showed a slight increase at the two highest doses of TCDD in field voles but not in bank voles, and their basal COH activity was only one-fourth or less of that in field voles. Overall, however, bank voles tended to exhibit higher CYP-associated enzyme activities measured at the two largest doses of TCDD than field voles. A western blot analysis of aryl hydrocarbon receptor (AhR) revealed that the two vole species had differential band patterns, suggesting dissimilar structures for their AhRs.

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Role of the AHR and its Structure in TCDD Toxicity

Cited by 19 publications

References 152 publications

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Hormones of Energy Balance in a TCDD-Sensitive and a TCDD-Resistant Rat Strain

Significant interspecies differences in induction profiles of hepatic CYP enzymes by TCDD in bank and field voles

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