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. 2009 May 15;117(11):1664–1672. doi: 10.1289/ehp.0900758

Figure 1.

Figure 1

(A) Hypothesized PPAR-α activation MOA as posited by Klaunig et al. (2003), with proposed “causal” events identified in green. (B) Is PPAR-α activation essential for DEHP carcinogenesis? Red outlines represent key events in the hypothesized PPAR-α activation MOA that were not induced by DEHP in PPAR-α–null mice despite the occurrence of tumors (Ito et al. 2007a; Ward et al. 1998). Proposed causal events are shaded pink. These key events are therefore not necessary for tumors, suggesting PPAR-α–independent pathways for DEHP hepatocarcinogenesis. (C) Is PPAR-α activation alone sufficient for carcinogenesis? In the Yang et al. (2007) LAP-VP16PPAR-α transgenic model of constitutive PPAR-α activation in hepatocytes, the key events in the hypothesized PPAR-α activation MOA (green outlines), but not tumors, are induced at 11 months. Proposed causal events in the MOA are shaded light green. Wy-14,643 exposure in wild-type mice induces tumors at 11 months with comparable levels of hepatocyte proliferation and other proposed key events. This raises questions about whether PPAR-α activation and hepatocyte proliferation can alone cause tumors, and suggests that the sequence of key events in the hypothesized MOA is not solely sufficient to evoke carcinogenesis. (D) Revisiting the PPAR-α activation MOA. DEHP is hepatocarcinogenic in PPAR-α–null mice in which the red-outlined key events are absent (Ito et al. 2007a; Ward et al. 1998), whereas, the green-outlined key events, but not tumors, are induced at 11 months in the LAP-VP16PPAR-α transgenic model (Yang et al. 2007). Proposed causal events are shaded light green. Taken together, these findings support the view that the hypothesized PPAR-α activation MOA is neither necessary nor sufficient for hepatocarcinogenesis as a sole causative factor.