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Key Event Title
Alterations, Cellular proliferation / hyperplasia
|Level of Biological Organization|
Key Event Components
|cell proliferation||Liver cell||abnormal|
|hyperplasia||hepatic oval stem cell||increased|
|hyperplasia||intrahepatic bile duct epithelial cell||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Sustained AhR Activation leading to Rodent Liver Tumours||KeyEvent||Rick Becker (send email)||Open for citation & comment||EAGMST Under Review|
Key Event Description
Over the time period of high levels of sustained AHR activation, DLCs produce a complex pattern of cell proliferative responses. Teeguarden et al. (1999) observed that rats initiated with diethylnitrosamine (DEN) and then dosed with either 0.1 or 1 ng/ kg-d TCDD for one month exhibited a reduced labeling index relative to controls, and reduced BrdU-labeling was also observed following the 0.1 ng/kg-d TCDD dose after three months. Maronpot et al. (1993) observed a reduction in BrdU labeling index in hepatocytes at a low dose of 3.5 ng/kg-d TCDD in DEN-initiated rats after 30 weeks of TCDD administration but, at a dose of 125 ng/kg/d the labeling index was increased.
Both parenchymal calls and liver stem cells are likely involved in the organ-level response to sustained AHR activation. Early acti- vation of the AHR in zone 3 of the liver acinus causes decreased hepatocyte replication and may act as an indirect proliferative stimulus for stem cells and hepatoblasts (Andersen et al., 1997; Conolly and Andersen, 1997; Tritscher et al., 1992). Oval cells in the periportal region likely function as a source of replacement of hepatocytes after inhibition of normal hepatocyte replication- replacement (Paku et al., 2001; Sahin et al., 2008; Tanaka et al., 2011; Wang et al., 2003). While hepatocyte replication is considered the normal means for replacement of liver parenchyma, inhibition of hepatocyte replication in centrilobular regions induced by TCDD may induce normally quiescent liver stem cells to proliferate.
Following longer period of sustained AHR activation, organ- level increases in cell proliferation ensue, demonstrated by an in- crease in BrdU labeling and likely reflecting the regenerative response to organ-wide toxicity (Hailey et al., 2005).
Non-parenchymal cells, including stem cells, hepatoblasts, biliary cells, stellate cells, endothelial cells, and Kuppfer cells, play a role in this AOP. In rodents, TCDD elicits a fibrogenic and bile duct proliferative response that requires pathological alteration of stellate cell function and increased differentiation and growth of hepatoblasts and bile duct cells before 33 weeks of exposure. Retinoid depletion induces stellate cell proliferation, production of extracellular matrix components, and the transition to fibroblast; stellate cells maintain vitamin A homeostasis and respond to liver injury with formation of proliferative cytokines such as TGF-a and EGF (Friedman, 2008; Pintilie et al., 2010; Senoo et al., 2010). TCDD induces loss of retinoid content (presumably from stellate cells) and may disrupt the extensive communication between various liver cell types (Fletcher et al., 2001; Hoegberg et al., 2005; Pierre et al., 2014; Schmidt et al., 2003). Thus, TCDD-induced retinol loss from hepatic stellate cells may contribute to cell proliferation, biliary fibrosis, and cholangiolarcarcinoma (Fattore et al., 2000; Friedman, 2008; Hakansson and Hanberg, 1989; Schmidt et al., 2003).
AHR activation also induces changes in stem/oval cells. All of the rats receiving 100 ng/kg/day TCDD, the highest dose group animals in the 2-year cancer bioassay, developed oval cell hyperplasia with clear statistical increases in this endpoint at 22 ng/kg/day or greater (Hailey et al., 2005). Evidence points to the involvement of TNF-alpha regulation in the proliferative response of hepatic stem cells; this is likely mediated through modulation of the levels of TNF-alpha, altered beta-catenin signaling, and inhibition of cell-to-cell contact (Knight et al., 2000; Umannova et al., 2007; Vondracek et al., 2009; Dietrich et al., 2002; Prochazkova et al.,2011; Weiss et al., 2008). TNF-alpha is an inflammatory cytokine with an important role in liver tumor promotion. More research on how sustained AHR activation dysregulates normal TNF-alpha activity could be very impactful on evolving the AOP.
How It Is Measured or Detected
Bile duct hyperplasia and oval cell hyperplasia are measured histopathological observations using frequency of occurrence and a severity index.
Domain of Applicability
The proliferative response of the liver appears to occur in rodents but not humans.
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Prochazkova, J., Kabatkova, M., Bryja, V., Umannova, L., Bernatík, O., Kozubík, A., Machala, M., Vondracek, J., 2011. The interplay of the aryl hydrocarbon receptor and b-catenin alters both AhR-dependent transcription and Wnt/b-catenin signaling in liver progenitors. Toxicol. Sci. 122, 349-360.
Sahin, M.B., Schwartz, R.E., Buckley, S.M., Heremans, Y., Chase, L., Hu, W.-S., Verfaillie, C.M., 2008. Isolation and characterization of a novel population of progenitor cells from unmanipulated rat liver. Liver Transpl. 14, 333-345.
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Wang, X., Foster, M., Al-Dhalimy, M., Lagasse, E., Finegold, M., Grompe, M., 2003. The origin and liver repopulating capacity of murine oval cells. Proc. Natl. Acad. Sci. U. S. A. 100 (Suppl. 1), 11881-11888.
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