Upstream eventActivation, Long term AHR receptor driven direct and indirect gene expression changes
Changes/Inhibition, Cellular Homeostasis and Apoptosis
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Sustained AhR Activation leading to Rodent Liver Tumours||adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
Sustained AHR activation inhibits apoptosis in altered hepatic foci (i.e., initiated hepatic cells), and this inhibition affords cells within altered hepatic foci a survival advantage and increases the likelihood that these cells will acquire additional mutations.
Evidence Supporting this KER
The weight of evidence descriptor for this KER is strong.
All the elements in this AOP are strongly associated with the biological steps and elements of carcinogenesis (Hanahan and Weinberg, 2011). First, there is extensive body of mechanistic evidence in support the biological plausibility of this MOA (see recent review by Budinsky et al., 2014). Further, the relationships between sustained AHR activation and changes in cellular growth homeostasis / apoptosis, has been used for many years in initiation-promotion studies to understand early events in tumor formation (Dragan et al. 1992; Dragan and Schrenk, 2000; Luebeck et al. 2000; Maronpot et al. 1993; Teeguarden et al. 1999).
AHR activation appears to cause inhibition of apoptosis in altered hepatic foci (Luebeck et al., 2000; Paajarvi et al., 2005; Schrenk et al., 1994, 2004; Stinchcombe et al., 1995). 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). Also, changes in cellular growth homeostasis / apoptosis are measured by changes in AHF reflecting changes in the apoptosis/proliferation balance occurs earliest in dose and time, reflected by the measure of SAA shown in the Dose-Time concordance table on the main page of this AOP.
Uncertainties and Inconsistencies
There are few, if any, uncertainties or inconsistencies regarding this KER.
Quantitative Understanding of the Linkage
Using the measure of SAA that incorporates both dose and time allows understanding of the quantitative relationship between the sustained AHR activation and changes in cellular growth homeostasis / apoptosis. Figure 4 shows a plot of the increase in volume fraction of ATPase-negative AHF versus sustained AHR activation. The Hill model fit to these data had an ESA50 value of 17.6.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of 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.
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, 83-119.
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.
Dragan, Y.P., Xu, X.H., Goldsworthy, T.L., Campbell, H.A., Maronpot, R.R., Pitot, H.C., 1992. Characterization of the promotion of altered hepatic foci by 2,3,7,8- tetrachlorodibenzo-p-dioxin in the female rat. Carcinogenesis 13, 1389-1395.
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.
Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell 144, 646-674.
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.
Maronpot, R.R., Foley, J.F., Takahashi, K., Goldsworthy, T., Clark, G., Tritscher, A., Portier, C., Lucier, G., 1993. Dose response for TCDD promotion of hep- atocarcinogenesis in rats initiated with DEN: histologic, biochemical, and cell proliferation endpoints 8. Environ. Heal. Perspect. 101, 634-642.
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.
Schrenk, D., Buchmann, A., Dietz, K., Lipp, H.P., Brunner, H., Sirma, H., Munzel, P., Hagenmaier, H., Gebhardt, R., Bock, K.W., 1994. Promotion of preneoplastic foci in rat liver with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8- heptachlorodibenzo-p-dioxin and a defined mixture of 49 polychlorinated dibenzo-p-dioxins. Carcinogenesis 15, 509-515.
Schrenk, D., Schmitz, H.J., Bohnenberger, S., Wagner, B., Worner, W., 2004. Tumor promoters as inhibitors of apoptosis in rat hepatocytes. Toxicol. Lett. 149, 43e50. 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.
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.