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

Guyton KZ, Chiu WA, Bateson TF, Jinot J, Scott CS, Brown RC, Caldwell JC - Environ. Health Perspect. (2009)

Bottom Line: We further examine whether relative potency for PPAR-alpha activation or other steps in the MOA correlates with tumorigenic potency.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.

View Article: PubMed Central - PubMed

Affiliation: National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA.

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- 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.

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(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– 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– 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.
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f1-ehp-117-1664: (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– 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– 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.

Mentions: Figure 1A shows a widely cited version of the hypothesized MOA for hepatocarcinogenesis induced by PPAR-α agonists, posited by Klaunig et al. (2003), in which three key causal events were proposed: activation of the receptor, perturbation of hepatocellular apoptosis and proliferation, and selective clonal expansion. Klaunig et al. (2003) concluded that PPAR-α activation represents a key event in the liver tumor MOA for DEHP. The evidential support included the in vitro demonstration of receptor activation by its monoester metabolite [mono-2-ethylhexyl phthalate (MEHP)] (Issemann and Green 1990; Maloney and Waxman 1999). In addition, peroxisome proliferation (or increased peroxisomal enzyme activity), an associative event in the MOA, was induced by tumorigenic doses of DEHP in the liver of mice and rats or by MEHP in rat hepatocytes (David et al. 1999; Gray et al. 1982, 1983; Hasmall et al. 1999; Mitchell et al. 1984, 1985; Reddy et al. 1986). Comparable to the results found for prototypical agonist [4-chloro-6-(2,3-xylidino)-2-pyrimidyl-thio]acetic acid (Wy-14,643), DEHP failed to induce peroxisomal enzymes and peroxisome proliferation in PPAR-α– mice with 24 weeks of exposure (Ward et al. 1998). This finding supported a causal role for receptor activation in peroxisome proliferation, but a study of the subsequent development of tumors by DEHP in PPAR-α– mice had not been conducted. However, Peters et al. (1997) had previously reported the absence of tumors in nine PPAR-α– mice exposed to Wy-14,643 at 11 months, whereas each of the six similarly exposed wild-type mice had multiple hepatocellular neoplasms. Based on this 11-month tumor bioassay of Wy-14,643 (Peters et al. 1997) and the short-term DEHP study (Ward et al. 1998) in PPAR-α– mice, it was assumed that “a long-term study of DEHP using PPAR-α– mice would provide the same results” (Klaunig et al. 2003). This assumption in turn supported the conclusion that “all the effects observed are due only to the activation of this receptor and the downstream events resulting from this activation and that no other modes of action are operant” (Klaunig et al. 2003).


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

Guyton KZ, Chiu WA, Bateson TF, Jinot J, Scott CS, Brown RC, Caldwell JC - Environ. Health Perspect. (2009)

(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– 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– 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.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2801168&req=5

f1-ehp-117-1664: (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– 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– 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.
Mentions: Figure 1A shows a widely cited version of the hypothesized MOA for hepatocarcinogenesis induced by PPAR-α agonists, posited by Klaunig et al. (2003), in which three key causal events were proposed: activation of the receptor, perturbation of hepatocellular apoptosis and proliferation, and selective clonal expansion. Klaunig et al. (2003) concluded that PPAR-α activation represents a key event in the liver tumor MOA for DEHP. The evidential support included the in vitro demonstration of receptor activation by its monoester metabolite [mono-2-ethylhexyl phthalate (MEHP)] (Issemann and Green 1990; Maloney and Waxman 1999). In addition, peroxisome proliferation (or increased peroxisomal enzyme activity), an associative event in the MOA, was induced by tumorigenic doses of DEHP in the liver of mice and rats or by MEHP in rat hepatocytes (David et al. 1999; Gray et al. 1982, 1983; Hasmall et al. 1999; Mitchell et al. 1984, 1985; Reddy et al. 1986). Comparable to the results found for prototypical agonist [4-chloro-6-(2,3-xylidino)-2-pyrimidyl-thio]acetic acid (Wy-14,643), DEHP failed to induce peroxisomal enzymes and peroxisome proliferation in PPAR-α– mice with 24 weeks of exposure (Ward et al. 1998). This finding supported a causal role for receptor activation in peroxisome proliferation, but a study of the subsequent development of tumors by DEHP in PPAR-α– mice had not been conducted. However, Peters et al. (1997) had previously reported the absence of tumors in nine PPAR-α– mice exposed to Wy-14,643 at 11 months, whereas each of the six similarly exposed wild-type mice had multiple hepatocellular neoplasms. Based on this 11-month tumor bioassay of Wy-14,643 (Peters et al. 1997) and the short-term DEHP study (Ward et al. 1998) in PPAR-α– mice, it was assumed that “a long-term study of DEHP using PPAR-α– mice would provide the same results” (Klaunig et al. 2003). This assumption in turn supported the conclusion that “all the effects observed are due only to the activation of this receptor and the downstream events resulting from this activation and that no other modes of action are operant” (Klaunig et al. 2003).

Bottom Line: We further examine whether relative potency for PPAR-alpha activation or other steps in the MOA correlates with tumorigenic potency.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.

View Article: PubMed Central - PubMed

Affiliation: National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA.

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- 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.

Show MeSH
Related in: MedlinePlus