Aryl hydrocarbon receptor, TCDD

Vorderstrasse, B.A., et. al., Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression, Toxicol. Appl. Pharmacol., 171, 157, 2001. 

Sulentic, C., Holsapple, M., and Kaminski, N., Putative link between transcriptional regulation of IgM expression by TCDD and the aryl hydrocarbon receptor/dioxin-responsive enhancer signaling pathway, J. Pharmacol. Exper. Therapeut., 295, 705, 2000. 

Kerkvliet, N. I., Shepherd, D. M., and Baecher-Steppan, L., T lymphocytes are direct, aryl hydrocarbon receptor (AhR)-dependent targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) AhR expression in both CD4+ and CD8+ T cells is necessary for full suppression of a cytotoxic T lymphocyte response by TCDD, Toxicol. Appl. Pharmacol., 185, 146, 2002. 

Funatake, C., et. al., Cutting Edge Activation of the aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) generates a population of CD4+CD25+ cells with characteristics of regulatory T cells, J. Immunol., 175, 4184, 2005. 

An essential step of TCDD toxic effects, including its carcinogenic potential, is its binding to the aryl hydrocarbon receptor (AhR) at the pM range. Deletion of... 

Figure 5.33 Mechanism of the receptor-mediated induction of CYP1A1 by a polycyclic hydrocarbon such as TCDD. The inducer-receptor (AhR) complex enters the nucleus, binds with ARNT, and the complex binds to the CYP1A1 gene in the DNA. This induces the production of CYP1A1 mRNA, which leads to the production of CYP1A1 protein and functional enzyme. Abbreviations AIP, AhR interacting protein AhR, aryl hydrocarbon receptor HSP, heat shock protein 90 ARNT, AhR nuclear translocator E.R., endoplasmic reticulum.

An additional screening test for TCDD-like (aryl hydrocarbon receptor, AhR, active) chemicals has been developed (Garrison et al. 1996) and is available commercially (Anonymous 1997). Dubbed the CALUX (for chemically activated luciferase gene expression) system, the assay is based on recombinant cell lines into which researchers have inserted a firefly luciferase gene. When exposed to dioxin-like compounds, the recombinant cells luminesce. The method is sensitive to ppt levels of 2,3,7,8-TCDD equivalents in blood, serum, and milk (Anonymous 1997). Samples testing positive can be subjected to more definitive and specific analytical testing. 

Ray S, Swanson HI (2009) Activation of the aryl hydrocarbon receptor by TCDD inhibits senescence a tumor promoting event Biochem Pharmacol 77 681-688... 

Figure 32.6. Model of AhR-mediated mechanism of action of TCDD and related HAHs. TCDD binds to the AhR in the cytoplasm. This complex interacts with another cytosolic protein (ARNT) and is translocated into the nucleus where it binds to specific DNA enhancer sequences upstream of TCDD responsive genes. Exactly which genes are important in the resulting immune suppression is unclear. Abbreviations AhR, aryl hydrocarbon receptor ARNT, AhR nuclear transporter DRE, dioxin-responsive elements.

Many of the toxic and biological effects induced by polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and PCBs such as carcinogenesis, reproductive disturbances and immunotoxic effects are believed to be mediated via the hepatic cytosolic aryl hydrocarbon receptor (Ah receptor) [254,255]. Based on in vitro and in vivo studies, the toxicity of individual organochlorines have been determined relative to 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD) and expressed as toxic equivalency factors (TEFs) [254, 256]. In addition to PCDD/F, structurally related PCBs and PCNs bind to the Ah receptor. After binding to the Ah-receptor, the receptor-ligand complex is transferred into the nucleus where it binds to specific DNA sequences and causes transcription of structural genes, which in turn causes synthesis of various cytochrome P4501A1-dependent enzymes such as ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH). TEFs for PCNs have been estimated from enzyme-induction assays of EROD and AHH [10, 257] and Luciferase assays in rat cells [12] cf. Table 4. 

UDP-glucuronosyltransferase, an enzyme that conjugates UDP-glucuronic acid with T4 and other steroid hormones, can be induced by TCDD via an aryl hydrocarbon receptor-dependent mechanism. In rats, TCDD exposure has been shown to increase the rate of removal of T4 from the blood. 

Perhaps the environmental chemical most studied with regard to effects on the immune system has been 2,3,7,8-tetrachlorodibenzo-p-dioxin, which is also known as TCDD or dioxin . While it appears that dioxin may affect multiple cell types, it is apparent that the B cell is an especially sensitive target. The mechanism of action for the immunotoxic effects of dioxin remains poorly understood. It is well established that many of the actions of dioxin, including inhibition of the primary antibody response, are mediated by a specific cytosolic receptor, termed the aryl hydrocarbon receptor (AhR). AhR exhibits a profile of activity similar to steroid receptors in that the ligand-activated receptor undergoes a nuclear... 

Abbreviations used in text AA, arachidonic acid AhR, aryl hydrocarbon receptor Amt, AhR nuclear translocator BR, bilirubin BV, biliverdin CYP1A1, cytochrome P4501A1 DRE, dioxin responsive element FICZ, 6-formylindolo(3,2b)carbazole HAH, halogenated aromatic hydrocarbon I3C, indole 3-carbinol ICZ, indolo-(3,2,-b)-carbazole PAH, polycyclic aromatic hydrocarbon RAR, retinoic acid receptor TCDD, 2,3,7,8-tetrachlorodi benzo-/>-dioxin Trp, tryptophan UGT 01, UDP-glucuronosy 1 transferase 01... 

Dioxin-like compounds are those chemicals that act as ligands for the aryl hydrocarbon receptor (AhR), which appears to be present in most vertebrate classes92. The AhR functions as a ligand-activated transcription factor and is responsible for most of the toxic consequences of dioxin-like compounds150, which can be diverse and include cardiovascular dysfunctions, immunosuppression and embryotoxicity24. Usually, the most potent ligand for the AhR and the most toxic compound is TCDD. Some important classes of ecotoxicants contain members that are AhR active (Table 4). 

Butler, R.B., M.L. Kelley, W.H. Powell, M.E. Hahn and R.J. Van Beneden. An aryl hydrocarbon receptor homologue from the soft-shell clam, Mya arenaria evidence that invertebrate AHR homologues lack TCDD and BNF binding. Gene 278 223-234, 2001. 

Peters, J.M., M.G. Narotsky, G. Elizondo, P.M. Fernandez-Salguero, F.J. Gonzalez and B.D. Abbott. Amelioration of TCDD-induced teratogenesis in aryl hydrocarbon receptor (AhR)-null mice. Toxicol. Sci. 47 86-92, 1999. 

Harper PA, Riddick DS, Okey AB (2006) Regulating the regulator factors that control levels and activity of the aryl hydrocarbon receptor. Biochem Pharmacol 72 267-279 Hassoun EA, Stohs SJ (1996) Comparative teratological studies on TCDD, endrin and lindane in C57BL/6J and DBA/2J mice. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 113 393-398... 

Hassoun EA, Walter AC, Alsharif NZ, Stohs SJ (1997) Modulation of TCDD-induced fetotoxicity and oxidative stress in embryonic and placental tissues of C57BL/6J mice by vitamin E succinate and ellagic acid. Toxicology 124 27-37 Hemandez-Ochoa I, Karman BN, Flaws JA (2009) The role of the aryl hydrocarbon receptor in the female reproductive system. Biochem Pharmacol 77 547-559 Hines RN (2008) The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther 118 250-267... 

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