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      Effect of a Large Dose of Di (2-ethylhexyl) phthalate (DEHP) on Hepatic Peroxisome in Cynomolgus Monkeys ( Macaca Fascicularis )

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          Abstract

          To elucidate the effect of a large dose of di (2-ethylhexyl) phthalate (DEHP), a plasticizer and peroxisome proliferator-activated receptor-α (PPARα) agonist, on hepatic peroxisomes, we orally administered 1,000 mg/kg/day, once daily, to 3 male and 4 female cynomolgus monkeys for 28 days consecutively. Light-microscopic and electron microscopic examinations of the liver were carried out in conjunction with measurement of the hepatic fatty acid β-oxidation system (FAOS), carnitine acetyltransferase (CAT) and carnitine palmitoyltransferase (CPT) activities, which are peroxisomal and/or mitochondrial enzyme activities. Electron microscopically, enlargement of the mitochondria was observed with lamellar orientation of the cristae along the major axis. Although the number of peroxisomes showed a tendency to increase when compared with those in a biopsied specimen before treatment, no abnormality in morphology was observed. A slight increase in CPT activity was noted at termination. No changes were noted in hepatic FAOS or CAT activity. In conclusion, although repeated oral treatment of cynomolgus monkeys with a large dose of DEHP induced a subtle increase in the numbers of peroxisomes with slight enlargements of the mitochondria, this low-sensitivity response to peroxisome proliferators in cynomolgus monkeys was considered to be closer to the response in humans than that in rodents.

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          Peroxisome proliferator-activated receptor-alpha and liver cancer: where do we stand?

          Marian Cheung, M Peters, J. Suarez Gonzalez (2005)
          The peroxisome proliferator-activated receptor-alpha (PPARalpha), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPARalpha is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPARalpha occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPARalpha agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPARalpha also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPARalpha. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPARalpha target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPARalpha in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPARalpha agonist-induced hepatocarcinogenesis.
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            A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA Risk Assessment Guidelines.

            John Doull, Russell C Cattley, Cliff Elcombe … (1999)
            The current United States Environmental Protection Agency (EPA) classification of di(2-ethylhexyl)phthalate (DEHP) as a B2 "probable human" carcinogen is based on outdated information. New toxicology data and a considerable amount of new mechanistic evidence were used to reconsider the cancer classification of DEHP under EPA's proposed new cancer risk assessment guidelines. The total weight-of-evidence clearly indicates that DEHP is not genotoxic. In vivo administration of DEHP to rats and mice results in peroxisome proliferation in the liver, and there is strong evidence and scientific consensus that, in rodents, peroxisome proliferation is directly associated with the onset of liver cancer. Peroxisome proliferation is a transcription-mediated process that involves activation by the peroxisome proliferator of a nuclear receptor in rodent liver called the peroxisome proliferator-activated receptor (PPARalpha). The critical role of PPARalpha in peroxisomal proliferation and carcinogenicity in mice is clearly established by the lack of either response in mice genetically modified to remove the PPARalpha. Several mechanisms have been proposed to explain how, in rodents, peroxisome proliferation can lead to the formation of hepatocellular tumors. The general consensus of scientific opinion is that PPARalpha-induced mitogenesis and cell proliferation are probably the major mechanisms responsible for peroxisome proliferator-induced hepatocarcinogenesis in rodents. Oxidative stress appears to play a significant role in this increased cell proliferation. It triggers the release of TNFalpha by Kupffer cells, which in turn acts as a potent mitogen in hepatocytes. Rats and mice are uniquely responsive to the morphological, biochemical, and chronic carcinogenic effects of peroxisome proliferators, while guinea pigs, dogs, nonhuman primates, and humans are essentially nonresponsive or refractory; Syrian hamsters exhibit intermediate responsiveness. These differences are explained, in part, by marked interspecies variations in the expression of PPARalpha, with levels of expression in humans being only 1-10% of the levels found in rat and mouse liver. Recent studies of DEHP clearly indicate a nonlinear dose-response curve that strongly suggests the existence of a dose threshold below which tumors in rodents are not induced. Thus, the hepatocarcinogenic effects of DEHP in rodents result directly from the receptor-mediated, threshold-based mechanism of peroxisome proliferation, a well-understood process associated uniquely with rodents. Since humans are quite refractory to peroxisomal proliferation, even following exposure to potent proliferators such as hypolipidemic drugs, it is concluded that the hepatocarcinogenic response of rodents to DEHP is not relevant to human cancer risk at any anticipated exposure level. DEHP should be classified an unlikely human carcinogen with a margin of exposure (MOE) approach to risk assessment. The most appropriate and conservative point of reference for assessing MOEs should be 20 mg/kg/day, which is the mouse NOEL for peroxisome proliferation and increased liver weight. Exposure of the general human population to DEHP is approximately 30 microg/kg body wt/day, the major source being from residues in food. Higher exposures occur occupationally [up to about 700 microg/kg body wt/day (mainly by inhalation) based on current workplace standards] and through use of certain medical devices [e.g., up to 457 microg/kg body wt/day for hemodialysis patients (intravenous)], although these have little relevance because the routes of exposure bypass critical activation enzymes in the gastrointestinal tract. Copyright 1999 Academic Press.
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              Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences.

              P Holden, J D Tugwood (1999)
              Peroxisome proliferators (PPs) are chemicals of industrial and pharmaceutical importance that elicit liver carcinogenesis by a non-genotoxic mechanism. One of the intriguing properties of PPs is that the pleiotropic effects of these compounds (including increased DNA synthesis and peroxisome proliferation) are seen in rats and mice only, but not humans. It is important to determine the risks to humans of environmental and therapeutic exposure to these compounds by understanding the mechanisms of non-genotoxic hepatocarcinogenesis in rodents. To understand this apparent lack of human susceptibility, attention has focused on the peroxisome proliferator-activated receptor alpha (PPARalpha), which appears to mediate the effects of PPs in rodents. It is also known to mediate the hypolipidaemic effects that fibrate drugs exert on humans with elevated plasma cholesterol and triglyceride levels. Human PPARalphas share many functional characteristics with the rodent receptors, in that they can be transcriptionally activated by PPs and regulate specific gene expression. However, one key difference is that PPARalpha is less abundant in human than in rodent liver, which has led to the suggestion that species differences result from quantitative differences in gene expression. In this review we describe the effects of PPs and what is known of the molecular mechanisms of action and species differences with respect to rodents and man. Attention will be given to differences in the amounts of PPARalpha between species as well as the 'qualitative' aspects of PPARalpha-mediated gene regulation which might also explain the activation of some genes and not of others in human liver by PPs.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Toxicol Pathol
                Journal ID (publisher-id): TOX
                Title: Journal of Toxicologic Pathology
                Publisher: The Japanese Society of Toxicologic Pathology
                ISSN (Print): 0914-9198
                ISSN (Electronic): 1881-915X
                Publication date (Print): June 2010
                Publication date (Electronic): 30 June 2010
                Volume: 23
                Issue: 2
                Pages: 75-83
                Affiliations
                [1 ]Shin Nippon Biomedical Laboratories Co., Ltd., 2438 Miyanoura Kagoshima-shi, Kagoshima 891-1394, Japan
                [2 ]Department of Veterinary Pathology, Faculty of Agriculture, Iwate University, 3–18–8 Ueda, Morioka-shi, Iwate 020-8550, Japan
                [3 ]The United Graduate School of Veterinary Sciences, Gifu University, 1–1 Yanagido, Gifu-shi, Gifu 501-1193, Japan
                Author notes
                Mailing address: Shigeru Satake, Shin Nippon Biomedical Laboratories Co., Ltd., 2438 Miyanoura Kagoshima-shi, Kagoshima 891-1394, Japan TEL: 81-19-623-7804 FAX: 81-19-623-7804 E-mail: satake-shigeru@ 123456snbl.co.jp
                Article
                Publisher ID: 0546
                DOI: 10.1293/tox.23.75
                PMC ID: 3234641
                PubMed ID: 22272015
                SO-VID: 1b430df9-92f7-4625-b145-3f18a8ac8b0f
                Copyright © 2010 The Japanese Society of Toxicologic Pathology
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License.

                History
                Date received : 06 October 2009
                Date accepted : 01 December 2009
                Categories
                Subject: Original

                ScienceOpen disciplines: Pathology
                Keywords: cynomolgus monkey,hepatocyte,di (2-ethylhexyl) phthalate (dehp),mitochondria,peroxisome
                Data availability:
                ScienceOpen disciplines: Pathology
                Keywords: cynomolgus monkey, hepatocyte, di (2-ethylhexyl) phthalate (dehp), mitochondria, peroxisome

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