A reexamination of the PPAR-alpha activation mode of action as a basis for assessing human cancer risks of environmental contaminants

Abstract

Background: Diverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-alpha agonists is irrelevant to human carcinogenic risk.

Data synthesis: Herein, we review recent studies that experimentally challenge the PPAR-alpha activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-alpha-null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-alpha activation in a transgenic mouse model. We further examine whether relative potency for PPAR-alpha activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-alpha agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis.

Conclusions: Our review and analyses raise questions about the hypothesized PPAR-alpha activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-alpha agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-alpha. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation.

Keywords: carcinogenesis; mode of action; peroxisome proliferators; risk assessment.

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.

Figure 2

Incidences of hepatocellular adenomas (A) and hepatocellular adenomas and carcinomas (B) in mice exposed to DEHP. Ito et al. (2007a) exposed PPAR-α–null (−/−) and wild-type (+/+) Sv129 mice for 22 months; David et al. (1999) exposed B6C3F1 wild-type (+/+) mice for up to 104 weeks. Data are presented as incidence ± SD assuming a binomial distribution for each group. All pairwise cross-study comparisons between like dose groups [e.g., Ito et al. 2007a (−/−) 500 ppm vs. David et al. (+/+) 500 ppm] were not significant by Fisher exact test. Because David et al. reported only adenomas and carcinomas, we excluded from analyses the cholangiocellular carcinoma reported by Ito et al. in DEHP-exposed PPAR-α–null mice. *Significantly different from controls of the same genotype in the same study (Fisher exact test, p < 0.05). **Significant trend with dose in the study (Cochran Armitage test, p < 0.05).