Aryl hydrocarbon receptor toxicity

Eernandez-Salguero, P.M., Hilbert, D.M., Rudikoff, S. et al. (1996). Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicology and Applied Pharmacology 140, 173-179. 

Marlowe, J.L. and Puga, A. (2005). Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. Journal of Cellular Biochemistry 96, 1174-1184. 

As observed in mammalian models, the immune system of fishes is a sensitive target organ system to evaluate toxicity. For a more thorough review of environmental immunotoxicology in fishes, with reference to specific classes of xenobiotics, readers are referred to several reviews that deal with the subject over a span of nearly three decades [45-47, 54-57], While fish in the environment may be exposed to a variety of xenobiotics, the most frequently investigated xenobiotics are the polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) due to the presence and activation of the aryl hydrocarbon receptor (AhR) in fish, and heavy metals due to their ubiquitous environmental distribution. 

Villeneuve, D.L. Crunkilton, R.L. DeVita, W.M. 1997, Aryl hydrocarbon receptor-mediated toxic potency of dissolved lipophilic organic contaminants collected from Lincoln Creek, Milwaukee, Wisconsin, USA, to PLHC-1 (Poeciliopsis lucida) fish hepatoma cells. Environ. Toxicol. Chem. 16 977-984. 

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... 

Prasch AL, Teraoka H, Camey SA, Dong W, Hiraga T, Stegeman JJ, Heideman W, Peterson RE (2003) Aryl hydrocarbon receptor 2 mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin developmental toxicity in zebrafish. Toxicol Sci 76 138-150... 

Polychlorinated hydrocarbons, such as polychlorinated dibenzodioxins, dibenzofurans, and biphenyls exist as a number of different congeners. Some of these are geometric isomers. Many cause a range of toxic effects that are believed to be mediated by interaction with the aryl hydrocarbon receptor (AhR) (they are known as pleiotropic effects). However, not all the isomers cause these effects because they do not all interact with the AhR receptor. To interact with this receptor, the molecule needs to be flat (planar). It can be seen in the diagram (Fig. 5.2)... 

Nebert DW. Role of the aryl hydrocarbon receptor mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem 2004 279 23847-23850. 

Aryl Hydrocarbon Receptor, and is the basis of the 2378-TeCDD TEQ additive toxicity model. Concentrations of AHR PCDD/Fs increased an order of magnitude downstream from the confluence of the Tittabawassee River, and increased a further order of magnitude in the lower reaches of the river, presumably because these were depositional zones. 

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. 

The potential toxicity of OH-PCBs was first investigated in the 1970s. Hydroxylated metabolites were reported having higher potencies for cell toxicity than their parent PCBs [64,193]. Phenolic PCB metabolites were also found to affect mitochondrial respiration and the permeability of the inner membrane. The nature of the effect depended on the structure and pKa of the phenolic metabolite [110,194]. Low binding potencies toward the aryl hydrocarbon receptor (AhR), and low induction capacity of ethoxyresorufin-O-deethylase (EROD), respectively, have been reported for phenolic PCB metabolites of non-ortho CB-77 and mono-ortho CB-105 [34, 195]. Dihydroxylated PCBs may be oxidized to quinones that in turn may react with macromolecules to form adducts, and cause oxidative stress leading to cell death [116]. 

Dibenzofuran induces hepatic, skin, and lung cytochrome P450 lAl, 1A2, and aryl hydrocarbon hydroxylase in rats. Thus, toxicity results from aryl hydrocarbon receptor signal transduction pathway. Bioactivation of many polycyclic hydrocarbon carcinogens is mediated by these enzymes. 

Kafafi SA, Afeefy HY, Said HK, Kafafi AG. 1993. Relationship between aryl hydrocarbon receptor binding, induction of aryl hydrocarbon hydroxylase and 7-ethyoxyresorufin o-deethylase enzymes and toxic activities of aromatic xenobi-otics in animals. A new model. Chem. Res. Toxicol. 6 328-34... 

The acute toxicity exerted by PCBs is generally low. The most prominent effect is the pronounced induction of the MFO system in different tissues, with increased de novo synthesis and increased levels in several cytP450 isozymes. The PCBs in the environment occur as a mixture of congeners and every congener exerts specific toxicity, with some PCBs exerting exclusive effects. One such effect is the capability for planar PCBs to bind to and stimulate the cytoplasmatic aryl hydrocarbon receptor in the cell, the same receptor that is stimulated by the highly toxic polychlorinated dibenzodioxins (PCDDs) (see below). 

Chopra M, Schrenk D (2011) Dioxin toxicity, aryl hydrocarbon receptor signaling, and apoptosis-persistent pollutants affect programmed cell death. Crit Rev Toxicol 41 (4) 292-320. doi 10.3109/10408444.20 10.524635... 

Abnet, C.C., R.L. Tanguay, W. Heideman and R.E. Peterson. Transactivation activity of human, zebrafish, and rainbow trout aryl hydrocarbon receptors expressed in COS-7 cells greater insight into species differences in toxic potency of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners. 

Tanguay, R.L., E. Andreasen, M.K. Walker and R.E. Peterson. Dioxin toxicity and aryl hydrocarbon receptor signaling in fish. In Dioxins and Health, 2nd ed., edited by T.A. Gasiewicz and A. Schecter, NewYork, Wiley, pp. 603—628, 2003, Chapter 15. 

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). 

Most of the research on xenobiotic receptors has been conducted in mammalian systems. These studies have identified three families of proteins as having important roles in regulating the response to xenobiotic chemicals (Table 1). The aryl hydrocarbon receptor (AHR), a member of the basic helix-loop-helix Per-ARNT-Sim (bHLH-PAS) family of transcription factors, is well known for its role in the altered gene expression and toxicity elicited by chlorinated dioxins and related planar halogenated aromatic hydrocarbons (PHAHs) as well as certain polynuclear aromatic hydrocarbons (PAHs)114 188 244. Several members of the nuclear/steroid... 

Bunger, M.K., S.M. Moran, E. Glover, T.L. Thomae, G.P. Lahvis, B.C. Lin and C.A. Bradfield. Resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and abnormal liver development in mice carrying a mutation in the nuclear localization sequence of the aryl hydrocarbon receptor. J. Biol. Chem. 278 17767-17774, 2003. 

Carney, S.A., W. Heideman and R.E. Peterson. 2,3,7,8-Tetrachlorodibenzo-p-dioxin activation of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator pathway causes developmental toxicity through a CYPlA-independent mechanism in zebrafish. Mol. Pharmacol 66 512-521, 2004. 

Cook, P.M., J.A. Robbins, D.D. Endicott, K.B. Lodge, P.D. Guiney, M.K. Walker, E.W. Zabel and R.E. Peterson. Effects of aryl hydrocarbon receptor-mediated early life stage toxicity on lake trout populations in Lake Ontario during the 20th century. Environ. Sci. Technol. 37 3864-3877, 2003. 

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