This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
Activation, Long term AHR receptor driven direct and indirect gene expression changes leads to Alterations, Cellular proliferation / hyperplasia
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Sustained AhR Activation leading to Rodent Liver Tumours||non-adjacent||High||High||Allie Always (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
Both the development of altered hepatic foci, which are preneoplastic lesions, and the highly proliferative environment induced in the liver by Hepatoxicity/Hepatopathy induce cell proliferation. Replacement of liver cells normally occurs by hepatocyte replication (Paku et al, 2001). However, Hepatoxicity/Hepatopathy may produce sufficient liver damage that stem cell replication also contributes to hepatocyte replacement (Alison, 2005). In general, increased stem cell replication appears to be associated with tumor formation (Tomasetti and Vogelstein, 2015).
Evidence Collection Strategy
Evidence Supporting this KER
The quantitative relationship discussed in the Sustained AHR Activation (MIE) page and also presented on the KER page for Sustained AHR Activation --> Hepatotoxicity/Hepatopathy is common to dioxin-like chemicals (NTP, 2006a, 2006b, 2006c, 2006d, 2006e, 2006f). In addition, rats fed indole-3-carbinol for eight weeks in an initiation-promotion medium term assay showed the development of oxidative stress, likely due to induction of CYP1A and other phase I enzymes. The development of AHF, here noted as Changes in Cellular Growth Homeostasis / Apoptosis was also enhanced (Shimamoto et al. 2011).
Uncertainties and Inconsistencies
While the exact mechanism of how sustained AHR activation leads to a strong hepato-proliferative response, a large number of observations lend certainty to the relationship.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This relationship occurs in rodents and possibly other animals but not in humans.
Alison, M.R., 2005. Liver stem cells: implications for hepatocarcinogenesis. Stem Cell Rev. 1, 253-260.
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.
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. 1-198.
NTP, 2006c. NTP toxicology and carcinogenesis studies of 3,3',4,4',5- pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (Gavage Studies). Natl. Toxicol. Program Tech. Rep. Ser. 4-246.
NTP, 2006d. NTP technical report on the toxicology and carcinogenesis studies of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) (CAS No. 35065-27-1) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 4-168.
NTP, 2006e. NTP toxicology and carcinogenesis studies of a binary mixture of 3,3' ,4,4' ,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. 1-258.
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 3,3',,4,4' ,5- pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 1-180.
Paku, S., Schnur, J., Nagy, P., Thorgeirsson, S.S., 2001. Origin and structural evolution of the early proliferating oval cells in rat liver. Am. J. Pathol. 158, 1313-1323.
Shimamoto, K., Dewa, Y., Ishii, Y., Kemmochi, S., Taniai, E., Hayashi, H., Imaoka, M., Morita, R., Kuwata, K., Suzuki, K., Shibutani, M., Mitsumori, K., 2011. Indole-3-carbinol enhances oxidative stress responses resulting in the induction of preneoplastic liver cell lesions in partially hepatectomized rats initiated with diethylnitrosamine. Toxicology. 283, 109-17.
Tomasetti, C., Vogelstein, B., 2015. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78-81.