Subchronic Toxicity of Di(2-ethylhexyl)phthalate in Common Marmosets: Lack of Hepatic Peroxisome Proliferation, Testicular Atrophy, or Pancreatic Acinar Cell Hyperplasia,

Kurata, Yoshimasa; Kidachi, Fumiyo; Yokoyama, Mitsue; Toyota, Naoto; Tsuchitani, Minoru; Katoh, Masanobu

doi:10.1006/toxs.1997.2414

Cited by 21 publications

(5 citation statements)

References 37 publications

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“…Several studies evaluated the pleiotropic responses to prolonged (from 14 days up to 13 weeks) oral administration of relatively high doses of peroxisome proliferators (500 to 2500 mg/kg) in several species of nonhuman primates [65–67]. In contrast to results found in rodents, no significant increases in liver weight, induction of peroxisomal enzymes, or proliferation of peroxisomes were reported.…”

Section: Resultsmentioning

confidence: 99%

Effects of the PPARαAgonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism

et al. 2010

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Gemfibrozil is a widely prescribed hypolipidemic agent in humans and a peroxisome proliferator and liver carcinogen in rats. Three-month feed studies of gemfibrozil were conducted by the National Toxicology Program (NTP) in male Harlan Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters, primarily to examine mechanisms of hepatocarcinogenicity. There was morphologic evidence of peroxisome proliferation in rats and mice. Increased hepatocyte proliferation was observed in rats, primarily at the earliest time point. Increases in peroxisomal enzyme activities were greatest in rats, intermediate in mice, and least in hamsters. These studies demonstrate that rats are most responsive while hamsters are least responsive. These events are causally related to hepatotoxicity and hepatocarcinogenicity of gemfibrozil in rodents via peroxisome proliferator activated receptor-α (PPARα) activation; however, there is widespread evidence that activation of PPARα in humans results in expression of genes involved in lipid metabolism, but not in hepatocellular proliferation.

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Section: Resultsmentioning

confidence: 99%

Effects of the PPARαAgonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism

et al. 2010

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“…In juvenile marmosets, exposure to DEHP at a daily dose as high as 2500 mg/kg for 13 or 65 weeks did not elicit any effect on the hormonal profiles nor the testicular histology (Kurata et al, 1998; Tomonari et al, 2006). Also, no effects were detected in the testicular histology of young adult cynomolgus monkeys exposed to 500 mg/kg/day of DEHP for 14 days (Pugh et al, 2000).…”

Section: Introductionmentioning

confidence: 83%

Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice

Rodriguez‐Sosa

Bondareva

Tang

et al. 2014

Molecular and Cellular Endocrinology

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Di-n-Butyl (DBP) and Di-(2-EthylHexyl) (DEHP) phthalates can leach from daily-use products resulting in environmental exposure. In male rodents, phthalate exposure results in reproductive effects. To evaluate effects on the immature primate testis, testis fragments from 6-month-old rhesus macaques were grafted subcutaneously to immune-deficient mice, which were exposed to 0, 10, or 500 mg/kg of DBP or DEHP for 14 weeks or 28 weeks (DBP only). DBP exposure reduced the expression of key steroidogenic genes, indicating that Leydig cell function was compromised. Exposure to 500 mg/kg impaired tubule formation and germ cell differentiation and reduced numbers of spermatogonia. Exposure to 10 mg/kg did not affect development, but reduced Sertoli cell number and resulted in increased expression of inhibin B. Exposure to DEHP for 14 week also affected steroidogenic genes expression. Therefore, long-term exposure to phthalate esters affected development and function of the primate testis in a time and dosage dependent manner.

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“…Several key or associative events in the hypothesized MOA have been observed directly in some but not all primate studies (Hoivik et al 2004; Ito et al 2007b; Kurata et al 1998). Studies of cultured primary human hepatocytes have generally reported little or no proliferative response to peroxisome proliferators (for reviews, see Ashby et al 1994; Peters et al 2005; Rusyn et al 2006).…”

Section: To What Extent Are Humans Sensitive To Ppar-α Agonists?mentioning

confidence: 99%

A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

Guyton

Chiu

Bateson

et al. 2009

Environ Health Perspect

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BackgroundDiverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator–activated receptor-α (PPAR-α) 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-α agonists is irrelevant to human carcinogenic risk.Data synthesisHerein, we review recent studies that experimentally challenge the PPAR-α activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-α–null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-α activation in a transgenic mouse model. We further examine whether relative potency for PPAR-α activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-α agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis.ConclusionsOur review and analyses raise questions about the hypothesized PPAR-α activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-α agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-α. 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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Subchronic Toxicity of Di(2-ethylhexyl)phthalate in Common Marmosets: Lack of Hepatic Peroxisome Proliferation, Testicular Atrophy, or Pancreatic Acinar Cell Hyperplasia,

Cited by 21 publications

References 37 publications

Effects of the PPARαAgonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism

Effects of the PPARαAgonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism

Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice

A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

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