API

Stressor: 20

Title

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Dioxin and dioxin-like compounds

Stressor Overview

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AOPs Including This Stressor

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This table is automatically generated and lists AOP’s including this stressor and their Evidence.



Events Including This Stressor

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Chemical Table

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User term DTXID Preferred name Casrn jchem_inchi_key indigo_inchi_key
2,3,7,8-tetrachlorodibenzo[b,e][1,4]dioxin DTXSID2021315 2,3,7,8-Tetrachlorodibenzo-p-dioxin 1746-01-6 HGUFODBRKLSHSI-UHFFFAOYSA-N HGUFODBRKLSHSI-UHFFFAOYSA-N
Acetamide DTXSID7020005 Acetamide 60-35-5 DLFVBJFMPXGRIB-UHFFFAOYSA-N DLFVBJFMPXGRIB-UHFFFAOYSA-N

AOP Evidence

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This table is automatically generated and includes the AOPs with this associated stressor as well as the evidence text from this AOP Stressor.



Event Evidence

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Activation, Long term AHR receptor driven direct and indirect gene expression changes

There is no evidence text for this event.




Stressor Info

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Chemical/Category Description

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The promiscuous nature of the AHR with its ability to bind to a large number of endogenous and exogenous ligands, make the task of constructing an AOP a challenge. For example, many structurally diverse chemicals can bind to and activate the AHR, including dioxin-like chemicals (DLCs), polyaromatic hydrocarbons (PAHs), indole-3-carbinol as found in broccoli and Brussels sprouts, natural flavonoids such as quercetin, galangin and genistein, and endogenous ligands such as indirubicin, equilenin, metabolites of arachidonic acid, heme, tryptophan, and UV photoproducts of tryptophan such as 6-formylindolo[3,2-b]carbazole (FICZ) [1] [2] [3]

It is believed, although not proven, that the endogenous and natural ligands ingested in the diet participate in normal homeostatic control of development and physiology through episodic and short-lived AHR activation. Developmental pathologies in AHR knockout rodents and toxicity associated with sustained AHR activation provide evidence that the AHR has a normal and necessary role. [1] [2] Weak agonists also include benzimidazoles such as omeprazole used pharmaceutically as a proton pump inhibitor and antihelminthics such as thiabendazole. Other weak agonists include primaquine, vinclozolin, YH439, phenylthiourea, curcumin and Oltipraz. [4] Therefore, a necessary task for this AOP is to differentiate between AHR ligands that act as rodent liver tumour promoters and those that do not. It may be that ligands resistant to metabolic clearance (e.g., TCDD), or sufficiently high doses of rapidly cleared ligands are able to create the sustained AHR activation required to bring about tumour promotion.

Chemical properties for a selection of AHR ligands are provided in Table 3 along with EC50, which itself is a measure of potency and one of the determinants of sustained AHR activation. These representative ligands demonstrate the diversity in chemical properties modelling pharmacokinetics and bioavailability as well as sources, including anthropogenic chemicals, dietary constituents, and endogenous substances formed in vivo. The determinants of sustained AHR activation include:

  • AHR binding potency, usually measured by an EC50 or ED50 value;
  • AHR binding efficacy or intrinsic activity measured by the maximal response;
  • pharmacokinetic determinants including,
    • Speed and extent of metabolism/elimination of a particular ligand;
    • Delivery to the target tissue; and,
  • Magnitude and duration of exposure.

Not all AHR ligands will produce sustained activation. Some ligands may stabilize the AHR, thus keeping it activated for longer times. [5] DLCs are highly hydrophobic and lipid soluble with half-lives in humans up to seven years or more. [6] Hence, a single high-dose exposure to a highly persistent compound such as TCDD can lead to sustained AHR activation sufficient to trigger some of the early responses. [7] In rodents, some of these high-dose responses may lead to the occurrence of KEs. [8] Exposure to lower doses over a long time may also produce sustained activation but may not culminate in increased tumour incidence. [9] Endogenous ligands have very different chemical characteristics than halogenated dibenzo-p-dioxins, dibenzofurans, and dioxin-like PCBs. The endogenous ligand FICZ is a more potent AHR agonist than TCDD but is rapidly metabolized by CYP1A1 in a negative feedback loop. As noted, control of AHR activation by endogenous ligands probably plays a role in development. [3] [10] [11]

Ideally, a table similar to Table 3 could be assembled with data on a range of diverse chemicals with results from common assays providing measures of potency, efficacy and metabolism. This information set may be of some utility in predicting the likelihood of a particular chemical to produce sustained AHR activation (the MIE). However, the use of structural alerts or QSAR considerations to predict the occurrence of the MIE remains an area of interest and may become more feasible in the future.
Table 3 alt text
Table 3: Application of the dose and temporal concordance Hill considerations for key events in rodents treated with TCDD


Characterization of Exposure

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Generally, AHR ligands are relatively large molecules with hydrophobic nature. Hence, these compounds have low volatility and are poorly absorbed through the skin. Therefore, the assumed route of exposure for this AOP is oral. The primary source of dioxin exposure in humans is animal-based food products, and the dioxin levels in foods have been declining over time. [12] [13] [14] [15] The dose of PCDD/Fs from dietary exposure can be expressed as TCDD toxic equivalents or TEQ. [16] Worldwide, this exposure has been estimated at less than 1 pg TEQ/kg/d. [17] [18] Exposures may be somewhat higher in populations consuming relatively more fish and shellfish. [19] Exposure to the remaining universe of exogenous and endogenous AHR ligands is not nearly as well characterised as is exposure to DLCs. A sampling of this universe consists of food products, substances in commercial and consumer products, phytoestrogens, prostaglandins, catechins in green tea, bilirubin and biliverdin, tryptophan, and its metabolites. [20] [21] [2] [1] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [10] [11] [32] [33] [34] Substantial AHR-activity has been reported in human serum and likely reflects many endogenous and naturally occurring AHR ligands from the diet. [35] The high level of background TEQ may serve as a ModF for the tumour promotion response to sustained AHR activation initiated by sufficient dosages of chlorinated dibenzo-p-dioxins, dibenzofurans and dioxin-like PCBs.



References

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  1. 1.0 1.1 1.2 Denison, M. S., Soshilov, A. A., He, G., DeGroot, D. E., and Zhao, B. (2011). Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol Sci 124(1), 1-22, 10.1093/toxsci/kfr218.
  2. 2.0 2.1 2.2 Denison, M. S., and Nagy, S. R. (2003). Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43, 309-34, 10.1146/annurev.pharmtox.43.100901.135828 100901.135828 [pii].
  3. 3.0 3.1 Gasiewicz, T. A., Henry, E. C., and Collins, L. L. (2008). Expression and activity of aryl hydrocarbon receptors in development and cancer. Crit Rev Eukaryot Gene Expr 18(4), 279-321, 4de8c9fe5b6af78b,714c550a3fb330d1 [pii].
  4. Nguyen, L. P., and Bradfield, C. A. (2008). The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21(1), 102-16, 10.1021/tx7001965.
  5. Bohonowych J.E. and Denison M.S., (2007) Persistent binding of ligands to the aryl hydrocarbon receptor Toxicol Sci 98, 99-109.
  6. Milbrath M.O., Wenger Y., Chang C.W., Emond C., Garabrant D., Gillespie B.W., and Jolliet O., (2009) Apparent half-lives of dioxins, furans, and polychlorinated biphenyls as a function of age, body fat, smoking status, and breast-feeding Environ Health Perspect 117, 417-25.
  7. Saurat J.H., Kaya G., Saxer-Sekulic N., Pardo B., Becker M., Fontao L., Mottu F., Carraux P., Pham X.C., Barde C., Fontao F., Zennegg M., Schmid P., Schaad O., Descombes P., and Sorg O., (2012) The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko Toxicol Sci 125, 310-7.
  8. Stinchcombe S., Buchmann A., Bock K.W., and Schwarz M., (1995) Inhibition of apoptosis during 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated tumour promotion in rat liver Carcinogenesis 16, 1271-1275.
  9. National Toxicology Program (NTP). (2006a) NTP technical report on the toxicology and carcinogenesis studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6) in female Harlan Sprague-Dawley rats (Gavage Studies) Natl Toxicol Program.Tech.Rep.Ser. 4-232.
  10. 10.0 10.1 Wincent E., Amini N., Luecke S., Glatt H., Bergman J., Crescenzi C., Rannug A., and Rannug U., (2009) The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans J Biol Chem 284, 2690-6.
  11. 11.0 11.1 Wincent E., Bengtsson J., Mohammadi Bardbori A., Alsberg T., Luecke S., Rannug U., and Rannug A., (2012) Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 109, 4479-84.
  12. Aylward L.L. and Hays S.M., (2002) Temporal trends in human TCDD body burden: decreases over three decades and implications for exposure levels J.Expo.Anal.Environ.Epidemiol. 12, 319-328.
  13. Hays S.M. and Aylward L.L., (2003) Dioxin risks in perspective: past, present, and future Regul.Toxicol.Pharmacol. 37, 202-217.
  14. Lorber M. (2002) A pharmacokinetic model for estimating exposure of Americans to dioxin-like compounds in the past, present, and future Sci.Total Environ. 288, 81-95.
  15. Lorber M., Patterson D., Huwe J., and Kahn H., (2009) Evaluation of background exposures of Americans to dioxin-like compounds in the 1990s and the 2000s Chemosphere 77, 640-51.
  16. Van den Berg M., Birnbaum L.S., Denison M., De V.M., Farland W., Feeley M., Fiedler H., Hakansson H., Hanberg A., Haws L., Rose M., Safe S., Schrenk D., Tohyama C., Tritscher A., Tuomisto J., Tysklind M., Walker N., and Peterson R.E., (2006) The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds Toxicol.Sci. 93, 223-241.
  17. Fromme H., Albrecht M., Boehmer S., Buchner K., Mayer R., Liebl B., Wittsiepe J., and Bolte G., (2009) Intake and body burden of dioxin-like compounds in Germany: the INES study Chemosphere 76, 1457-63.
  18. Windal I., Vandevijvere S., Maleki M., Goscinny S., Vinkx C., Focant J.F., Eppe G., Hanot V., and Van Loco J., (2010) Dietary intake of PCDD/Fs and dioxin-like PCBs of the Belgian population Chemosphere 79, 334-40.
  19. Nakatani T., Yamamoto A., and Ogaki S., (2010) A Survey of Dietary Intake of Polychlorinated Dibenzo-p-dioxins, Polychlorinated Dibenzofurans, and Dioxin-like Coplanar Polychlorinated Biphenyls from Food During 2000-2002 in Osaka City, Japan Arch Environ Contam Toxicol, 10.1007/s00244-010-9553-y.
  20. Ahn K.C., Zhao B., Chen J., Cherednichenko G., Sanmarti E., Denison M.S., Lasley B., Pessah I.N., Kultz D., Chang D.P., Gee S.J., and Hammock B.D., (2008) In vitro biologic activities of the antimicrobials triclocarban, its analogs, and triclosan in bioassay screens: receptor-based bioassay screens Environ Health Perspect 116, 1203-10.
  21. Bohonowych J.E., Zhao B., Timme-Laragy A., Jung D., Di Giulio R.T., and Denison M.S., (2008) Newspapers and newspaper ink contain agonists for the ah receptor Toxicol Sci 102, 278-90.
  22. El Gendy M.A.M., Soshilov A.A., Denison M.S., and El-Kadi A.O.S., (2012) Harmaline and harmalol inhibit the carcinogen-activating enzyme CYP1A1 via transcriptional and posttranslational mechanisms. Food Chem Toxicol 50, 353-62.
  23. Heath-Pagliuso S., Rogers W.J., Tullis K., Seidel S.D., Cenijn P.H., Brouwer A., and Denison M.S., (1998) Activation of the Ah receptor by tryptophan and tryptophan metabolites Biochemistry 37, 11508-15.
  24. Hu W., Sorrentino C., Denison M.S., Kolaja K., and Fielden M.R., (2007) Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro Mol Pharmacol 71, 1475-86.
  25. Jeuken A., Keser B.J., Khan E., Brouwer A., Koeman J., and Denison M.S., (2003) Activation of the Ah receptor by extracts of dietary herbal supplements, vegetables, and fruits J Agric Food Chem 51, 5478-87.
  26. Knockaert M., Blondel M., Bach S., Leost M., Elbi C., Hager G.L., Nagy S.R., Han D., Denison M., Ffrench M., Ryan X.P., Magiatis P., Polychronopoulos P., Greengard P., Skaltsounis L., and Meijer L., (2004) Independent actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate the antiproliferative effects of indirubins Oncogene 23, 4400-12.
  27. Lawrence B.P., Denison M.S., Novak H., Vorderstrasse B.A., Harrer N., Neruda W., Reichel C., and Woisetschlager M., (2008) Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound Blood 112, 1158-65.
  28. Phelan D., Winter G.M., Rogers W.J., Lam J.C., and Denison M.S., (1998) Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin Arch Biochem Biophys 357, 155-63.
  29. Seidel S.D., Winters G.M., Rogers W.J., Ziccardi M.H., Li V., Keser B., and Denison M.S., (2001) Activation of the Ah receptor signaling pathway by prostaglandins J Biochem Mol Toxicol 15, 187-96.
  30. Tiong C.T., Chen C., Zhang S.J., Li J., Soshilov A., Denison M.S., Lee L.S.-U., Tam V.H., Wong S.P., Xu H.E., and Yong E.-L., (2012) A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein. Carcinogenesis 33, 1089-97.
  31. Williams S.N., Shih H., Guenette D.K., Brackney W., Denison M.S., Pickwell G.V., and Quattrochi L.C., (2000) Comparative studies on the effects of green tea extracts and individual tea catechins on human CYP1A gene expression Chem Biol Interact 128, 211-29.
  32. Zhao B., Baston D.S., Hammock B., and Denison M.S., (2006) Interaction of diuron and related substituted phenylureas with the Ah receptor pathway J Biochem Mol Toxicol 20, 103-13.
  33. Zhao B., Degroot D.E., Hayashi A., He G., and Denison M.S., (2010) CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor. Toxicol Sci 117, 393-403.
  34. Zhao B., Bohonowych J.E.S., Timme-Laragy A., Jung D., Affatato A.A., Rice R.H., Di Giulio R.T., and Denison M.S., (2013) Common commercial and consumer products contain activators of the aryl hydrocarbon (dioxin) receptor. PLoS One 8, e56860.
  35. Connor K.T., Harris M.A., Edwards M.R., Budinsky R.A., Clark G.C., Chu A.C., Finley B.L., and Rowlands J.C., (2008) AH receptor agonist activity in human blood measured with a cell-based bioassay: evidence for naturally occurring AH receptor ligands in vivo J Expo Sci Environ Epidemiol 18, 369-80.