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Event Title

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

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Sustained AhR Activation leading to Rodent Liver Tumours MIE Strong

Chemical Initiators

The following are chemical initiators that operate directly through this Event:

  1. Dioxin and dioxin-like compounds

Taxonomic Applicability

Name Scientific Name Evidence Links
Rattus sp. ABTC 42503 Rattus sp. ABTC 42503 Strong NCBI
mouse Mus musculus Strong NCBI

Level of Biological Organization

Biological Organization

How this Key Event works

MIE: Macromolecular Interactions and Sustained Ligand-Activation of Transcription

Insight into sustained AHR activation is provided by examining the induction of ethoxyresorufin-O,O-deethylase in liver by three DLCs at three different time points (NTP, 2006a; NTP, 2006b; NTP, 2006c). Plots of the fractional or normalized ethoxyresorufin-O,O- deethylase response from three NTP cancer bioassays are shown in the plots on the left of Fig. 2. Induction of ethoxyresorufin-O,O- deethylase is easily measured and serves as a biomarker of CYP1A1 gene expression. The dose term on the x-axis is the area under the curve (AUC) of liver concentration. The normalized ethoxyresorufin-O,O-deethylase response on the y-axis is similar at 14, 31 and 53 weeks (Left column of Fig. 2). The plots for 31 weeks and 53 weeks are shifted to the right given the dose term on the x-axis is the AUC of hepatic concentration of the three chemicals, TCDD, 4-PeCDF and PCB-126. To obtain a measure of sustained AHR activation, the fractional ethoxyresorufin-O,O- deethylase response is multiplied by the number of weeks. Hence, a fractional response of 50% at 14 weeks would be a sustained AHR activation index of 7. The sustained AHR activation index is plotted versus the AUC of hepatic toxic equivalents (TEQ) for all three chemicals calculated using TEF values of 1.0, 0.3 and 0.1 for TCDD, 4-PeCDF and PCB-126 respectively (Van den Berg et al., 2006) (Fig. 2, right column). The sustained AHR activation index shows a strong relationship to the AUC of hepatic TEQ and thus the sustained AHR activation index reflects the dose, potency and duration of DLCs in the liver.

Dose-response modeling can be performed using the sustained AHR activation index as the dose term and the measures of the various KEs or biomarkers as the response. Fig. 4 shows an example in which the well-known Hill dose-response model was used. One of the model parameters is the ED50 or EC50 value e in other words, the effective dose or concentration sufficient to produce a 50% of the maximal response. This parameter is also called the half- maximal dose. When this measure of sustained AHR activation is used, the ESA50 denotes the level of sustained AHR activation required for a half-maximal response.

Please also see Becker, R.A., Patlewicz, G., Simon, T.W., Rowlands, J.C., Budinsky, R.A. 2015. The adverse outcome pathway for rodent liver tumor promotion by sustained activation of the aryl hydrocarbon receptor. Regul. Toxicol. Pharmacol. 73, 172-190: PMID: 26145830. The file is open access.

How it is Measured or Detected

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Dose-response modeling can be performed using the sustained AHR activation index as the dose term and the measures of the various KEs or biomarkers as the response. Figure 3 shows an example in which the well-known Hill dose-response model was used. One of the model parameters is the ED50 or EC50 value e in other words, the effective dose or concentration sufficient to produce a 50% of the maximal response. This parameter is also called the half- maximal dose. When this measure of sustained AHR activation is used, the ESA50 denotes the level of sustained AHR activation required for a half-maximal response.

Figure 2
Figure 2 alt text
Figure 2: Dose-response of CYP1A1 activation measured by EROD as a measure of AHR activation in response to an AUC measure of dose. The AUC is the hepatic concentration multiplied by the time in weeks. The left hand plots show measured EROD from the NTP bioassays in response to chronic dosing of TCDD (top), 4-PeCDF (middle) or PCB-126 (bottom) (NTP, 2006a, 2006b, 2006c). Dose-dependent EROD levels are sustained over time. The right hand plots show the EROD response on normalized to a zero-to-one scale as a measure of AHR activation level.
shows plots of the increase in 7-Ethoxyresorufin-O-deethylase (EROD) versus the area-under-the-curve (AUC) of the hepatic concentration of three dioxin-like chemicals, TCDD, 4-PeCDF and PCB-126 occurring during lifetime dosing. The figure shows corresponding plots of normalized EROD as a measure of AHR activation. In all three cases, the shape of the dose-response remained consistent except that the position along the dose axis increased with increasing time for all three chemicals. This observation indicates that the level of AHR activation remains relatively constant over time with a continuing dose of persistent AHR ligand. A measure of sustained activation (SA) of the AHR can be calculated by multiplying the level of AHR activation observed as fractional CYP1A1 induction by the number of weeks of dosing. SA calculated in this way can be used as a dose surrogate. In order to use the measurements of all three DLCs considered here, their hepatic AUC concentrations were multiplied by their toxic equivalence factors (TEFs) (Van den Berg et al., 2006). SA was plotted against the AUC of hepatic TEQ concentration (Figure 3).
Figure 3 alt text
Figure 3: Sustained AHR activation versus the area-under-the-curve of hepatic TEQ. TEQ was calculated for TCDD, PeCDF and PCB126 using TEF values of 1, 0.3 and 0.1 respectively. Data from all three chemicals at 14 weeks are shown with blue markers, those from 31 weeks with green markers and those from 53 weeks with orange markers. Please see narrative for additional details.
The plot shows a consistent pattern that can be fit with a Hill function. The curve is shallower than a first-order Hill plot shown by the Hill coefficient less than one. This shallowness may be due to differences in potency and efficacy at different times, possibly stemming from hepatic sequestration of ligand by CYP1A2, especially for PeCDF, thus decreasing the effective hepatic concentration relative to the measured concentration.

Evidence Supporting Taxonomic Applicability

At a number of levels of biological organization, differences exist between the human and rodent AHR. Considering toxicodynamics, the human AHR binding affinity is an order of magnitude or more lower than that in rodents that is generally correlated with reduced sensitivity in human hepatocytes relative to rats (Black et al., 2012; Budinsky et al., 2010; Connor and Aylward, 2006). In addition, these species differences include AHR binding affinity, different recruit- ment of co-regulatory proteins, and different patterns of gene regulation (Black et al., 2012; Budinsky et al., 2010; Carlson et al., 2009; Connor and Aylward, 2006; Dere et al., 2011; Flaveny et al., 2010).


Abel, J., Haarmann-Stemmann, T., 2010. An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol. Chem. 391, 1235e1248. http:// dx.doi.org/10.1515/BC.2010.128.

Andersen, M.E., Preston, R.J., Maier, A., Willis, A.M., Patterson, J., 2014. Dose- response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: results of a workshop. Crit. Rev. Toxicol. 44, 50e63. http:// dx.doi.org/10.3109/10408444.2013.835785.

Angrish, M.M., Jones, A.D., Harkema, J.R., Zacharewski, T.R., 2011. Aryl hydrocarbon receptor-mediated induction of stearoyl-CoA desaturase 1 alters hepatic fatty acid composition in TCDD-elicited steatosis. Toxicol. Sci. 124, 299e310. http:// dx.doi.org/10.1093/toxsci/kfr226.

Beischlag, T.V., Luis Morales, J., Hollingshead, B.D., Perdew, G.H., 2008. The aryl hydrocarbon receptor complex and the control of gene expression. Crit. Rev. Eukaryot. Gene. Expr. 18, 207e250, 6f28b0540a5e6e63,5ec7b3e06964879d [pii].

Bendall, S.C., Nolan, G.P., 2012. From single cells to deep phenotypes in cancer. Nat. Biotechnol. 30, 639e647. http://dx.doi.org/10.1038/nbt.2283.

Black, M.B., Budinsky, R.A., Dombkowski, A., Lecluyse, E.L., Ferguson, S.S., Thomas, R.S., Rowlands, J.C., 2012. Cross-species comparisons of transcriptomic alterations in human and rat primary hepatocytes exposed to 2,3,7,8- tetrachlorodibenzo-p-dioxin. Toxicol. Sci. 127, 199e215. http://dx.doi.org/ 10.1093/toxsci/kfs069.

Boutros, P.C., Bielefeld, K.A., Pohjanvirta, R., Harper, P.A., 2009. Dioxin-dependent and dioxin-independent gene batteries: comparison of liver and kidney in AHR- null mice. Toxicol. Sci. 112, 245e256 kfp191 [pii] 10.1093/toxsci/kfp191.

Boutros, P.C., Moffat, I.D., Franc, M.A., Tijet, N., Tuomisto, J., Pohjanvirta, R., Okey, A.B., 2004. Dioxin-responsive AHRE-II gene battery: identification by phylogenetic footprinting. Biochem. Biophys. Res. Commun. 321, 707e715.

Boutros, P.C., Yao, C.Q., Watson, J.D., Wu, A.H., Moffat, I.D., Prokopec, S.D., Smith, A.B., Okey, A.B., Pohjanvirta, R., 2011. Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity. Toxicol. Appl. Pharmacol. 251, 119e129. http://dx.doi.org/10.1016/ j.taap.2010.12.010. S0041-008X(10)00467-9 [pii].

Boverhof, D.R., Burgoon, L.D., Tashiro, C., Chittim, B., Harkema, J.R., Jump, D.B., Zacharewski, T.R., 2005. Temporal and dose-dependent hepatic gene expression patterns in mice provide new insights into TCDD-Mediated hepatotoxicity. Toxicol. Sci. 85, 1048e1063.

Boverhof, D.R., Burgoon, L.D., Tashiro, C., Sharratt, B., Chittim, B., Harkema, J.R., Mendrick, D.L., Zacharewski, T.R., 2006. Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice. Toxicol. Sci. 94, 398e416.

Brauze, D., Rawłuszko, A.A., 2012. The effect of aryl hydrocarbon receptor ligands on the expression of polymerase (DNA directed) kappa (Polk), polymerase RNA II (DNA directed) polypeptide A (PolR2a), CYP1B1 and CYP1A1 genes in rat liver. Environ. Toxicol. Pharmacol. 34, 819e825. http://dx.doi.org/10.1016/ j.etap.2012.09.004.

Budinsky, R.A., LeCluyse, E.L., Ferguson, S.S., Rowlands, J.C., Simon, T., 2010. Human and rat primary hepatocyte CYP1A1 and 1A2 induction with 2,3,7,8- tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8- pentachlorodibenzofuran. Toxicol. Sci. 118, 224e235 kfq238 [pii] 10.1093/ toxsci/kfq238.

Budinsky, R.A., Schrenk, D., Simon, T., Van den Berg, M., Reichard, J.F., Silkworth, J.B., Aylward, L.L., Brix, A., Gasiewicz, T., Kaminski, N., Perdew, G., Starr, T.B., Walker, N.J., Rowlands, J.C., 2014. Mode of action and dose-response framework analysis for receptor-mediated toxicity: the aryl hydrocarbon receptor as a case study. Crit. Rev. Toxicol. 44, 83e119. http://dx.doi.org/10.3109/ 10408444.2013.835787.

Connor, K.T., Aylward, L.L., 2006. Human response to dioxin: aryl hydrocarbon re- ceptor (AhR) molecular structure, function, and dose-response data for enzyme induction indicate an impaired human AhR. J. Toxicol. Environ. Health B Crit. Rev. 9, 147e171.

Carlson, E.A., McCulloch, C., Koganti, A., Goodwin, S.B., Sutter, T.R., Silkworth, J.B., 2009. Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes. Toxicol. Sci. 112, 257e272. http:// dx.doi.org/10.1093/toxsci/kfp200 kfp200 [pii].

Chia, N.-Y., Ng, H.-H., 2012. Stem cell genome-to-systems biology. Wiley Interdiscip. Rev. Syst. Biol. Med. 4, 39e49. http://dx.doi.org/10.1002/wsbm.151.

Dere, E., Lee, A.W., Burgoon, L.D., Zacharewski, T.R., 2011. Differences in TCDD- elicited gene expression profiles in human HepG2, mouse Hepa1c1c7 and rat H4IIE hepatoma cells. BMC Genomics 12, 193. http://dx.doi.org/10.1186/1471- 2164-12-193.

Denison, M.S., Soshilov, A.A., He, G., DeGroot, D.E., 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, 1e22. http:// dx.doi.org/10.1093/toxsci/kfr218.

Dietrich, C., Kaina, B., 2010. The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth. Carcinogenesis 31, 1319e1328. http:// dx.doi.org/10.1093/carcin/bgq028 bgq028 [pii].

Ellinger-Ziegelbauer, H., Gmuender, H., Bandenburg, A., Ahr, H.J., 2008. Prediction of a carcinogenic potential of rat hepatocarcinogens using toxicogenomics analysis of short-term in vivo studies. Mutat. Res. 637, 23e39. http://dx.doi.org/10.1016/ j.mrfmmm.2007.06.010.

Ellinger-Ziegelbauer, H., Stuart, B., Wahle, B., Bomann, W., Ahr, H.J., 2005. Com- parison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver. Mutat. Res. 575, 61e84. http://dx.doi.org/10.1016/ j.mrfmmm.2005.02.004.

Fielden, M.R., Adai, A., Dunn, R.T., Olaharski, A., Searfoss, G., Sina, J., Aubrecht, J., Boitier, E., Nioi, P., Auerbach, S., Jacobson-Kram, D., Raghavan, N., Yang, Y., Kincaid, A., Sherlock, J., Chen, S.-J., Car, B., Predictive Safety Testing Consortium, Carcinogenicity Working Group, 2011. Development and evaluation of a genomic signature for the prediction and mechanistic assessment of non- genotoxic hepatocarcinogens in the rat. Toxicol. Sci. 124, 54e74. http:// dx.doi.org/10.1093/toxsci/kfr202.

Fielden, M.R., Brennan, R., Gollub, J., 2007. A gene expression biomarker provides early prediction and mechanistic assessment of hepatic tumor induction by nongenotoxic chemicals. Toxicol. Sci. 99, 90e100. http://dx.doi.org/10.1093/ toxsci/kfm156.

Flaveny, C.A., Murray, I.A., Perdew, G.H., 2010. Differential gene regulation by the human and mouse aryl hydrocarbon receptor. Toxicol. Sci. 114, 217e225. http:// dx.doi.org/10.1093/toxsci/kfp308 kfp308 [pii].

Fletcher, N., Wahlstrom, D., Lundberg, R., Nilsson, C.B., Nilsson, K.C., Stockling, K., Hellmold, H., Hakansson, H., 2005. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the mRNA expression of critical genes associated with cholesterol metabolism, bile acid biosynthesis, and bile transport in rat liver: a microarray study. Toxicol. Appl. Pharmacol. 207, 1e24.

Forgacs, A.L., Burgoon, L.D., Lynn, S.G., LaPres, J.J., Zacharewski, T., 2010. Effects of TCDD on the expression of nuclear encoded mitochondrial genes. Toxicol. Appl. Pharmacol. 246, 58e65. http://dx.doi.org/10.1016/j.taap.2010.04.006. S0041- 008X(10)00133-X [pii].

Franc, M.A., Moffat, I.D., Boutros, P.C., Tuomisto, J.T., Tuomisto, J., Pohjanvirta, R., Okey, A.B., 2008. Patterns of dioxin-altered mRNA expression in livers of dioxin- sensitive versus dioxin-resistant rats. Arch. Toxicol. 82, 809e830. http:// dx.doi.org/10.1007/s00204-008-0303-0.

Furness, S.G., Whelan, F., 2009. The pleiotropy of dioxin toxicityexenobiotic misappropriation of the aryl hydrocarbon receptor's alternative physiological roles. Pharmacol. Ther. 124, 336e353. http://dx.doi.org/10.1016/j.pharm- thera.2009.09.004. S0163-7258(09)00187-9 [pii].

Gasiewicz, T.A., Henry, E.C., Collins, L.L., 2008. Expression and activity of aryl hy- drocarbon receptors in development and cancer. Crit. Rev. Eukaryot. Gene Expr. 18, 279e321, 4de8c9fe5b6af78b,714c550a3fb330d1 [pii].

George, C.L., Lightman, S.L., Biddie, S.C., 2011. Transcription factor interactions in genomic nuclear receptor function. Epigenomics 3, 471e485. http://dx.doi.org/ 10.2217/epi.11.66.

Hailey, J.R., Walker, N.J., Sells, D.M., Brix, A.E., Jokinen, M.P., Nyska, A., 2005. Clas- sification of proliferative hepatocellular lesions in harlan sprague-dawley rats chronically exposed to dioxin-like compounds. Toxicol. Pathol. 33, 165e174. http://dx.doi.org/10.1080/01926230590888324. TBE21PK0FLEJ66J7 [pii].

Harrill, J.A., Hukkanen, R.R., Lawson, M., Martin, G., Gilger, B., Soldatow, V., Lecluyse, E.L., Budinsky, R.A., Rowlands, J.C., Thomas, R.S., 2013. Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice. Toxicol. Appl. Pharmacol. 272, 503e518. http://dx.doi.org/ 10.1016/j.taap.2013.06.024.

Heise, T., Schug, M., Storm, D., Ellinger-Ziegelbauer, H., Ahr, H.J., Hellwig, B., Rahnenfuhrer, J., Ghallab, A., Guenther, G., Sisnaiske, J., Reif, R., Godoy, P., Mielke, H., Gundert-Remy, U., Lampen, A., Oberemm, A., Hengstler, J.G., 2012. In vitro e in vivo correlation of gene expression alterations induced by liver carcinogens. Curr. Med. Chem. 19, 1721e1730.

Ikeda, H., Nishi, S., Sakai, M., 2004. Transcription factor Nrf2/MafK regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis. Bio- chem.. J. 380, 515e521. http://dx.doi.org/10.1042/BJ20031948.

Jaramillo, M.C., Zhang, D.D., 2013. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes. Dev. 27, 2179e2191. http://dx.doi.org/10.1101/gad.225680.113.

Julien, E., Boobis, A.R., Olin, S.S., Ilsi Research Foundation Threshold Working Group, 2009. The key events dose-response framework: a cross-disciplinary mode-of- action based approach to examining dose-response and thresholds. Crit. Rev. Food. Sci. Nutr. 49, 682e689. http://dx.doi.org/10.1080/10408390903110692.

Kumar, M.B., Ramadoss, P., Reen, R.K., Vanden Heuvel, J.P., Perdew, G.H., 2001. The Q-rich subdomain of the human Ah receptor transactivation domain is required for dioxin-mediated transcriptional activity. J. Biol. Chem. 276, 42302e42310. http://dx.doi.org/10.1074/jbc.M104798200. M104798200 [pii].

Kumar, R., Wang, R.-A., Barnes, C.J., 2004. Coregulators and chromatin remodeling in transcriptional control. Mol. Carcinog. 41, 221e230. http://dx.doi.org/ 10.1002/mc.20056.

Kwak, M.K., Itoh, K., Yamamoto, M., Sutter, T.R., Kensler, T.W., 2001. Role of tran- scription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3- thione. Mol. Med. 7, 135e145.

Le Vee, M., Jouan, E., Fardel, O., 2010. Involvement of aryl hydrocarbon receptor in basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced expression of target genes in primary human hepatocytes. Toxicol. In Vitro 24, 1775e1781. http:// dx.doi.org/10.1016/j.tiv.2010.07.001.

Lee, K.C., Lee Kraus, W., 2001. Nuclear receptors, coactivators and chromatin: new approaches, new insights. Trends Endocrinol. Metab. 12, 191e197.

Lees, M.J., Whitelaw, M.L., 1999. Multiple roles of ligand in transforming the dioxin receptor to an active basic helix-loop-helix/PAS transcription factor complex with the nuclear protein Arnt. Mol. Cell. Biol. 19, 5811e5822.

Liby, K.T., Sporn, M.B., 2012. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol. Rev. 64, 972e1003. http://dx.doi.org/10.1124/ pr.111.004846.

Lu, H., Cui, W., Klaassen, C.D., 2011. Nrf2 protects against 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)-induced oxidative injury and steatohepatitis. Toxicol. Appl. Pharmacol. 256, 122e135. http://dx.doi.org/10.1016/j.taap.2011.07.019.

Ma, Q., Baldwin, K.T., Renzelli, A.J., McDaniel, A., Dong, L., 2001. TCDD-inducible poly(ADP-ribose) polymerase: a novel response to 2,3,7,8-tetrachlorodibenzo- p-dioxin. Biochem. Biophys. Res. Commun. 289, 499e506. http://dx.doi.org/ 10.10 06/bbrc.20 01.5987.

Ma, Q., 2011. Influence of light on aryl hydrocarbon receptor signaling and conse- quences in drug metabolism, physiology and disease. Expert. Opin. Drug. Metab. Toxicol. 7, 1267e1293. http://dx.doi.org/10.1517/17425255.2011.614947.

Ma, Q., He, X., 2012. Molecular basis of electrophilic and oxidative defense: promises and perils of Nrf2. Pharmacol. Rev. 64, 1055e1081. http://dx.doi.org/ 10.1124/pr.110.004333.

Matthews, J., Gustafsson, J.A., 2006. Estrogen receptor and aryl hydrocarbon re- ceptor signaling pathways. Nucl. Recept. Signal 4, e016. http://dx.doi.org/ 10.1621/nrs.04016.

Matthews, J., Wihlen, B., Thomsen, J., Gustafsson, J.A., 2005. Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor alpha to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters. Mol. Cell Biol. 25, 5317e5328. http://dx.doi.org/10.1128/MCB.25.13.5317- 5328.2005, 25/13/5317 [pii].

Moffat, I.D., Boutros, P.C., Chen, H., Okey, A.B., Pohjanvirta, R., 2010. Aryl hydro- carbon receptor (AHR)-regulated transcriptomic changes in rats sensitive or resistant to major dioxin toxicities. BMC Genomics 11, 263. http://dx.doi.org/ 10.1186/1471-2164-11-263.

Nie, A.Y., McMillian, M., Parker, J.B., Leone, A., Bryant, S., Yieh, L., Bittner, A., Nelson, J., Carmen, A., Wan, J., Lord, P.G., 2006. Predictive toxicogenomics ap- proaches reveal underlying molecular mechanisms of nongenotoxic carcino- genicity. Mol. Carcinog. 45, 914e933. http://dx.doi.org/10.1002/mc.20205.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. 4e232.

NTP, 2006b. NTP toxicology and carcinogenesis studies of 2,3,4,7,8- Pentachlorodibenzofuran (PeCDF) (CAS No. 57117-31-4) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 1e198.

NTP, 2006c. NTP toxicology and carcinogenesis studies of 3,30,4,40,5- pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (Gavage Studies). Natl. Toxicol. Program Tech. Rep. Ser. 4e246.

NTP, 2006d. NTP technical report on the toxicology and carcinogenesis studies of 2,20,4,40,5,50-hexachlorobiphenyl (PCB 153) (CAS No. 35065-27-1) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 4E168.

NTP, 2006e. NTP toxicology and carcinogenesis studies of a binary mixture of 3,30 ,4,40 ,5-Pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) and 2,20,4,40,5,50-Hexachlorobiphenyl (PCB 153) (CAS No. 35065-27-1) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 1E258.

NTP, 2006f. NTP toxicology and carcinogenesis studies of a mixture of 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6), 2,3,4,7,8- pentachlorodibenzofuran (PeCDF) (CAS No. 57117-31-4), and 3,30 ,4,40 ,5- pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 1E180.

NTP, 2010. Toxicology and carcinogenesis studies of 2,30 ,4,40 ,5-pentachlorobiphenyl (PCB 118) (CAS No. 31508-00-6) in female harlan Sprague-Dawley rats (gavage studies). Natl. Toxicol. Program. Tech. Rep. Ser. 1E174.

Osburn, W.O., Yates, M.S., Dolan, P.D., Chen, S., Liby, K.T., Sporn, M.B., Taguchi, K., Yamamoto, M., Kensler, T.W., 2008. Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol. Sci. 104, 218e227. http://dx.doi.org/10.1093/toxsci/kfn079.

Ovando, B.J., Ellison, C.A., Vezina, C.M., Olson, J.R., 2010. Toxicogenomic analysis of exposure to TCDD, PCB126 and PCB153: identification of genomic biomarkers of exposure to AhR ligands, BMC. Genomics 11, 583. http://dx.doi.org/10.1186/ 1471-2164-11-583, 1471-2164-11-583 [pii].

Ovando, B.J., Vezina, C.M., McGarrigle, B.P., Olson, J.R., 2006. Hepatic gene down- regulation following acute and subchronic exposure to 2,3,7,8- tetrachlorodibenzo-p-dioxin. Toxicol. Sci. 94, 428e438.

Partch, C.L., Gardner, K.H., 2010. Coactivator recruitment: a new role for PAS do- mains in transcriptional regulation by the bHLH-PAS family. J. Cell. Physiol. 223, 553e557. http://dx.doi.org/10.1002/jcp.22067.

Perissi, V., Rosenfeld, M.G., 2005. Controlling nuclear receptors: the circular logic of cofactor cycles. Nat. Rev. Mol. Cell. Biol. 6, 542e554. http://dx.doi.org/10.1038/ nrm1682.

Reen, R.K., Cadwallader, A., Perdew, G.H., 2002. The subdomains of the trans- activation domain of the aryl hydrocarbon receptor (AhR) inhibit AhR and es- trogen receptor transcriptional activity. Arch. Biochem. Biophys. 408, 93e102.

Rowlands, J.C., McEwan, I.J., Gustafsson, J.A., 1996. Trans-activation by the human aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator proteins: direct interactions with basal transcription factors. Mol. Pharmacol. 50, 538e548.

Rowlands, J.C., Budinsky, R., Gollapudi, B., Novak, R., Abdelmegeed, M., Cukovic, D., Dombkowski, A., 2011. Transcriptional profiles induced by the Aryl hydrocarbon receptor agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8- tetrachlorodibenzofuran and 2,3,4,7,8-pentachlorodibenzofuran in primary rat hepatocytes. Chemosphere. http://dx.doi.org/10.1016/j.chemo- sphere.2011.06.026. S0045e6535(11)00669-2 [pii].

Sato, S., Shirakawa, H., Tomita, S., Tohkin, M., Gonzalez, F.J., Komai, M., 2013. The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A. Toxicol. Appl. Pharmacol. 273, 90e99. http://dx.doi.org/ 10.1016/j.taap.2013.08.017.

Shelton, P., Jaiswal, A.K., 2013. The transcription factor NF-E2-related factor 2 (Nrf2): a protooncogene? FASEB. J. 27, 414e423. http://dx.doi.org/10.1096/fj.12-217257.

Simon, T.W., Simons, S.S., Preston, R.J., Boobis, A.R., Cohen, S.M., Doerrer, N.G., Fenner-Crisp, P.A., McMullin, T.S., McQueen, C.A., Rowlands, J.C., RISK21 Dose- Response Subteam, 2014. The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events. Crit. Rev. Toxicol. 44 (Suppl. 3), 17e43. http:// dx.doi.org/10.3109/10408444.2014.931925.

Soshilov, A., Denison, M.S., 2011. Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain. J. Biol. Chem. 286, 35275e35282. http://dx.doi.org/10.1074/ jbc.M111.246439.

Tanaka, M., Itoh, T., Tanimizu, N., Miyajima, A., 2011. Liver stem/progenitor cells: their characteristics and regulatory mechanisms. J. Biochem. 149, 231e239. http://dx.doi.org/10.1093/jb/mvr001.

Tappenden, D.M., Hwang, H.J., Yang, L., Thomas, R.S., Lapres, J.J., 2013. The aryl- hydrocarbon receptor protein interaction network (AHR-PIN) as identified by tandem affinity purification (TAP) and mass spectrometry. J. Toxicol. 2013, 279829. http://dx.doi.org/10.1155/2013/279829.

Tsai, C.-C., Fondell, J.D., 2004. Nuclear receptor recruitment of histone-modifying enzymes to target gene promoters. Vitam. Horm. 68, 93e122. http:// dx.doi.org/10.1016/S0083-6729(04)68003-4.

van Delft, J.H.M., van Agen, E., van Breda, S.G.J., Herwijnen, M.H., Staal, Y.C.M., Kleinjans, J.C.S., 2005. Comparison of supervised clustering methods to discriminate genotoxic from non-genotoxic carcinogens by gene expression profiling. Mutat. Res. 575, 17e33. http://dx.doi.org/10.1016/ j.mrfmmm.2005.02.006.

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., 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, 223e241.

Vezina, C.M., Walker, N.J., Olson, J.R., 2004. Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression. Environ. Heal. Perspect. 112, 1636e1644.

Wang, L., He, X., Szklarz, G.D., Bi, Y., Rojanasakul, Y., Ma, Q., 2013. The aryl hydro- carbon receptor interacts with nuclear factor erythroid 2-related factor 2 to mediate induction of NAD(P)H:quinoneoxidoreductase 1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Arch. Biochem. Biophys. 537, 31e38. http:// dx.doi.org/10.1016/j.abb.2013.06.001.

Watanabe, T., Suzuki, T., Natsume, M., Nakajima, M., Narumi, K., Hamada, S., Sakuma, T., Koeda, A., Oshida, K., Miyamoto, Y., Maeda, A., Hirayama, M., Sanada, H., Honda, H., Ohyama, W., Okada, E., Fujiishi, Y., Sutou, S., Tadakuma, A., Ishikawa, Y., Kido, M., Minamiguchi, R., Hanahara, I., Furihata, C., 2012. Discrimination of genotoxic and non-genotoxic hepatocarcinogens by statistical analysis based on gene expression profiling in the mouse liver as determined by quantitative real-time PCR. Mutat. Res. 747, 164e175. http:// dx.doi.org/10.1016/j.mrgentox.2012.04.011.

Yao, C.Q., Prokopec, S.D., Watson, J.D., Pang, R., P'ng, C., Chong, L.C., Harding, N.J., Pohjanvirta, R., Okey, A.B., Boutros, P.C., 2012. Inter-strain heterogeneity in rat hepatic transcriptomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol. Appl. Pharmacol. 260, 135e145. http://dx.doi.org/10.1016/ j.taap.2012.02.001.

Yates, M.S., Kensler, T.W., 2007. Keap1 eye on the target: chemoprevention of liver cancer. Acta Pharmacol. Sin. 28, 1331e1342. http://dx.doi.org/10.1111/j.1745- 7254.2007.00688.x.

Yates, M.S., Tauchi, M., Katsuoka, F., Flanders, K.C., Liby, K.T., Honda, T., Gribble, G.W., Johnson, D.A., Johnson, J.A., Burton, N.C., Guilarte, T.R., Yamamoto, M., Sporn, M.B., Kensler, T.W., 2007. Pharmacodynamic characterization of che- mopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol. Cancer Ther. 6, 154e162. http://dx.doi.org/10.1158/1535-7163.MCT- 06-0516.

Zhang, Q., Andersen, M.E., 2007. Dose response relationship in anti-stress gene regulatory networks. PLoS Comput. Biol. 3, e24. http://dx.doi.org/10.1371/ journal.pcbi.0030024.