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Event Title

Cellular Homeostasis and Apoptosis, Changes/Inhibition

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 KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
rat Rattus norvegicus NCBI
mouse Mus musculus NCBI

Level of Biological Organization

Biological Organization

How this Key Event works

Tumor promotion requires a perturbation in the balance between cell gain via mitosis and cell loss via apoptosis (Roberts et al., 1997). Indirectly, the inhibition of apoptosis in either damaged or initiated cells favors their survival, and inhibition of apoptosis af- fords initiated cells an increased opportunity for clonal expansion and autonomous growth with the chance to acquire additional mutations during the process of tumor progression. AHR activation inhibits apoptosis in altered hepatic foci (i.e., initiated hepatic cells), and this inhibition affords cells within altered hepatic foci a sur- vival advantage and increases the likelihood that these cells will acquire additional mutations.

How it is Measured or Detected

For this KE, initiation-promotion studies provide indirect evidence of inhibition of intrafocal apoptosis due to sustained AHR activation and direct evidence of a threshold for the clonal expansion of altered hepatic foci (Dragan and Schrenk, 2000; Teeguarden et al., 1999). Although increases of cell proliferation could contribute to the increase in size and volume fraction of altered hepatic foci, the greater magnitude of inhibition of apoptosis suggests it is the primary factor contributing to clonal expansion of altered hepatic foci, at least early on (Luebeck et al., 2000; Moolgavkar et al., 1996; Stinchcombe et al., 1995). AHR activators inhibit apoptosis produced by UV light exposure of human cell lines and rat primary hepatocytes (Ambolet-Camoit et al., 2010; Chopra et al., 2009, 2010; Schwarz et al., 2000). Inhibition of apoptosis in primary rat hepatocytes was mediated through phosphorylation and inactivation of p53 and modulation of Mdm2, Tfgb1/4, and AGR2; in addition, inhi- bition of apoptosis required protein synthesis (Ambolet-Camoit et al., 2010; Chopra and Schrenk, 2011; Chopra et al., 2009, 2010; Davis et al., 2001; Franc et al., 2008; Paajarvi et al., 2005; Worner and Schrenk, 1996, 1998). Cytotoxicity appears to occur after intrafocal apoptosis inhibition is measured and inflammation-driven cell proliferation is a somewhat later event. What remains unknown is whether a proliferative response in stem and stellate cells occurs earlier or at the same time as intrafocal apoptosis inhibition.

Quantitative stereology is used to quantify the growth of AHF and such studies provide a measure of this KE (Hendrich et al., 1987; Dragan et al., 1997; Teeguarden et al., 1999; Viluksela et al., 2000).

Evidence Supporting Taxonomic Applicability

Rodents are highly susceptible to the hepatotoxic, proliferative, and carcinogenic effects of sustained AHR activation induced by TCDD and other dioxin-like chemicals (Hailey et al., 2005; Goodman and Sauer, 1992; Kociba et al., 1978). The sustained AHR activation rodent liver tumor promotion AOP appears to be a pathway that very likely requires exceedance of a threshold for sustained AHR activation for liver cancers to occur in rodents.


Ambolet-Camoit, A., Bui, L.C., Pierre, S., Chevallier, A., Marchand, A., Coumoul, X., Garlatti, M., Andreau, K., Barouki, R., Aggerbeck, M., 2010. 2,3,7,8- tetrachlorodibenzo-p-dioxin counteracts the p53 response to a genotoxicant by upregulating expression of the metastasis marker agr2 in the hep- atocarcinoma cell line HepG2. Toxicol. Sci. 115, 501-512.

Chopra, M., Dharmarajan, A.M., Meiss, G., Schrenk, D., 2009. Inhibition of UV-C light-induced apoptosis in liver cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Sci. 111, 49-63.

Chopra, M., Gahrs, M., Haben, M., Michels, C., Schrenk, D., 2010. Inhibition of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin depends on protein biosyn- thesis. Cell Biol. Toxicol. 26, 391-401.

Chopra, M., Schrenk, D., 2011. Dioxin toxicity, aryl hydrocarbon receptor signaling, and apoptosis-Persistent pollutants affect programmed cell death. Crit. Rev. Toxicol. 41:292-320.

Davis W., J.W., Lauer, F.T., Burdick, A.D., Hudson, L.G., Burchiel, S.W., 2001. Prevention of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the MCF-10A cell line: correlation with increased transforming growth factor alpha production. Cancer. Res. 61, 3314-3320.

Dragan, Y. P., Campbell, H. A., Xu, X. H., Pitot, H. C., 1997. Quantitative stereological studies of a 'selection' protocol of hepatocarcinogenesis following initiation in neonatal male and female rats. Carcinogenesis. 18, 149-58.

Dragan, Y.P., Schrenk, D., 2000. Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion. Food. Addit. Contam. 17, 289-302.

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, 809-830.

Goodman, D.G., Sauer, R.M., 1992. Hepatotoxicity and carcinogenicity in female Sprague-Dawley rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): a pathology working group reevaluation. Regul. Toxicol. Pharmacol. 15, 245-252.

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, 165-174.

Hendrich, S., Campbell, H. A., Pitot, H. C., 1987. Quantitative stereological evaluation of four histochemical markers of altered foci in multistage hepatocarcinogenesis in the rat. Carcinogenesis. 8, 1245-50.

Kociba, R.J., Keyes, D.G., Beyer, J.E., Carreon, R.M., Wade, C.E., Dittenber, D.A., Kalnins, R.P., Frauson, L.E., Park, C.N., Barnard, S.D., Hummel, R.A., Humiston, C.G., 1978. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol. Appl. Pharmacol. 46, 279-303.

Luebeck, E.G., Buchmann, A., Stinchcombe, S., Moolgavkar, S.H., Schwarz, M., 2000. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on initiation and promotion of GST-P-positive foci in rat liver: a quantitative analysis of experimental data using a stochastic model. Toxicol. Appl. Pharmacol. 167, 63-73.

Moolgavkar, S.H., Luebeck, E.G., Buchmann, A., Bock, K.W., 1996. Quantitative analysis of enzyme-altered liver foci in rats initiated with diethylnitrosamine and promoted with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 1,2,3,4,6,7,8- heptachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 138, 31-42.

Paajarvi, G., Viluksela, M., Pohjanvirta, R., Stenius, U., Hogberg, J., 2005. TCDD ac- tivates Mdm2 and attenuates the p53 response to DNA damaging agents. Carcinogenesis 26, 201-208.

Roberts, R.A., Nebert, D.W., Hickman, J.A., Richburg, J.H., Goldsworthy, T.L., 1997. Perturbation of the mitosis/apoptosis balance: a fundamental mechanism in toxicology. Fundam. Appl. Toxicol. 38, 107-115.

Schwarz, M., Buchmann, A., Stinchcombe, S., Kalkuhl, A., Bock, K., 2000. Ah receptor ligands and tumor promotion: survival of neoplastic cells. Toxicol. Lett. 112e113, 69-77.

Stinchcombe, S., Buchmann, A., Bock, K.W., Schwarz, M., 1995. Inhibition of apoptosis during 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated tumour pro- motion in rat liver. Carcinogenesis 16, 1271-1275.

Teeguarden, J.G., Dragan, Y.P., Singh, J., Vaughan, J., Xu, Y.H., Goldsworthy, T., Pitot, H.C., 1999. Quantitative analysis of dose- and time-dependent promotion of four phenotypes of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p- dioxin in female Sprague-Dawley rats. Toxicol. Sci. 51, 211-223.

Viluksela, M., Bager, Y., Tuomisto, J. T., Scheu, G., Unkila, M., Pohjanvirta, R., Flodstrom, S., Kosma, V. M., Maki-Paakkanen, J., Vartiainen, T., Klimm, C., Schramm, K. W., Warngard, L., Tuomisto, J., 2000. Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains 27. Cancer Res. 60, 6911-6920.

Worner, W., Schrenk, D., 1996. Influence of liver tumor promoters on apoptosis in rat hepatocytes induced by 2-acetylaminofluorene, ultraviolet light, or transforming growth factor beta 1. Cancer. Res. 56, 1272-1278.