Receptor and Nonreceptor-Mediated Organ-Specific Toxicity of Di(2-ethylhexyl)phthalate (DEHP) in Peroxisome Proliferator-Activated Receptorα-Null Mice

Ward, Jerrold M.; Peters, Jeffrey M.; Perella, Christine M.; Gonzalez, Frank J.

doi:10.1177/019262339802600208

Cited by 237 publications

(166 citation statements)

References 19 publications

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“…DEHP-induced glomerulonephritis was found for the first time in this study. The known DEHP tubulointerstitial toxicities, reported in previous studies using high dosages of DEHP in short-term periods (14,22), did not appear in our study. The discrepancy in renal pathology between the earlier studies and this study probably is derived from differences in study design.…”

Section: Discussioncontrasting

confidence: 79%

“…These tubulointerstitial lesions were localized around the sclerotic glomerular lesions (Figure 3). The lesions, reported in earlier studies, such as cystic tubular dilation, tubular necrosis, tubular pigmentation, and papillary mineralization (14,22), were scarcely detected here. These findings suggest that secondary tubulointerstitial lesions developed after glomerular damages occurred.…”

Section: Dehp Induces Immune-complex Glomerulonephritiscontrasting

confidence: 72%

“…DEHP, a peroxisome proliferator, was reported to cause primarily PPAR␣-dependent toxicity in rodents but is considered to be relatively safe in humans. However, some studies have associated DEHP with PPAR␣-independent renal and testicular toxicities (14,15); accordingly, the mechanisms of DEHP toxicity as well as the reliability of DEHP safety assessments that have been conducted to date remain controversial.…”

Section: I-(2-ethylhexyl)phthalate (Dehp)mentioning

confidence: 99%

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Peroxisome Proliferator–Activated Receptor α Protects against Glomerulonephritis Induced by Long-Term Exposure to the Plasticizer Di-(2-Ethylhexyl)Phthalate

Kamijo¹,

Hora²,

Nakajima³

et al. 2007

Journal of the American Society of Nephrology

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Safety concerns about di-(2-ethylhexyl)phthalate (DEHP), a plasticizer and a probable endocrine disruptor, have attracted considerable public attention, but there are few studies about long-term exposure to DEHP. DEHP toxicity is thought to involve peroxisome proliferator-activated receptor ␣ (PPAR␣), but this contention remains controversial. For investigation of the long-term toxicity of DEHP and determination of whether PPAR␣ mediates toxicity, wild-type and PPAR␣-null mice were fed a diet that contained 0.05 or 0.01% DEHP for 22 mo. PPAR␣-null mice that were exposed to DEHP exhibited prominent immune complex glomerulonephritis, most likely related to elevated glomerular oxidative stress. Elevated NADPH oxidase, low antioxidant enzymes, and absence of the PPAR␣-dependent anti-inflammatory effects that normally antagonize the NFB signaling pathway accompanied the glomerulonephritis in PPAR␣-null mice. The results reported here indicate that PPAR␣ protects against the nephrotoxic effects of long-term exposure to DEHP. , a probable endocrine disruptor, is used widely as a plasticizer for production of many types of polyvinyl chloride (PVC) consumer products. DEHP provides PVC items with the desired mechanical properties, including flexibility and strength. The presence of DEHP in the environment has been confirmed, as has product-related human exposure to DEHP; recent safety assessments of DEHP thereby have attracted much public interest (1). DEHP continually enters the human body via food, water, and the atmosphere. Moreover, substantial human exposure to DEHP occurs via PVC-containing medical devices that are used in intravenous therapy, enteral and parenteral nutrition support, blood transfusion, hemodialysis, cardiopulmonary bypass, and extracorporeal membrane oxygenation (2). Maximal medical exposure has been estimated to be near the US no-observed-adverse-effect level (3.7 to 14 mg/kg body wt per d). Many previous experimental animal studies yielded no obvious evidence of DEHP toxicities at these low exposure levels, but periods of exposure in the studies generally were brief. Long-term exposure to DEHP is important for safety assessment of real-world toxicity.Past experimental animal studies using short-term exposure to high-dosage DEHP have demonstrated hepatotoxicity, testicular toxicity, renal toxicity, developmental disturbance, reproductive toxicity, and teratogenicity (3-5). The peroxisome proliferator-activated receptor ␣ (PPAR␣), a member of the steroid/nuclear receptor superfamily of ligand-dependent transcription factors, has been implicated as a causative factor in these toxicities (6). PPAR␣ is expressed abundantly in the rodent liver, testis, kidney, heart, digestive tract, and retina (7) and participates in diverse physiologic functions, including maintenance of lipid and glucose homeostasis (8 -11), regulation of cell proliferation (12), and modulation of inflammatory responses (13). In humans, some ligands for this receptor, termed peroxisome proliferators, are used clinically as hypolipid...

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Section: Discussioncontrasting

confidence: 79%

Section: Dehp Induces Immune-complex Glomerulonephritiscontrasting

confidence: 72%

Section: I-(2-ethylhexyl)phthalate (Dehp)mentioning

confidence: 99%

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Peroxisome Proliferator–Activated Receptor α Protects against Glomerulonephritis Induced by Long-Term Exposure to the Plasticizer Di-(2-Ethylhexyl)Phthalate

Kamijo¹,

Hora²,

Nakajima³

et al. 2007

Journal of the American Society of Nephrology

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“…The relatively recent development of PPARa gene knockout mice has now confirmed that the PPARa receptor is responsible for mediating the effects induced by the peroxisome proliferator-inducing agents clofibrate, WY-14,643 and DEHP (i.e., hepatomegaly, increases in peroxisomes and enzyme induction) (Lee et al 1995;Ward et al 1998). It is also responsible for the transient increase in cell proliferation commonly observed immediately after treatment as well as the more variable low level sustained increases in proliferation occasionally observed following chronic treatment (Cattley 2004).…”

Section: The Role Of the Ppara Receptormentioning

confidence: 99%

Liver Hypertrophy

Elcombe²,

et al. 2012

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Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARa. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

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“…In parallel, interaction of some phthalate metabolites with PPARa are responsible for in vivo effects, such as malformations in the male reproductive tract and liver cancer in mice and rats. 40,49,50 Amazingly, fairly little is known on the metabolic consequences of phthalate exposure. Therefore, we addressed the issue of interference of EDCs with PPARregulated processes using the MEHP metabolite of the DEHP plasticizer as a model.…”

Section: Pparc and Phthalates: Stepping In With The Definition Of A Smentioning

confidence: 99%

Interference of pollutants with PPARs: endocrine disruption meets metabolism

2008

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The concept of endocrine disruption emerged over a decade ago with the observation that several natural or industrial compounds can interfere with estrogen and androgen signaling, and thereby affect both male and female reproductive functions. Since then, many endocrine-disrupting chemicals (EDCs) have been identified and the concept has been broadened to receptors regulating other aspects of endocrine pathways. In that context, interference of EDCs with receptors regulating metabolism has been proposed as a factor that could contribute to metabolic diseases such as obesity and diabetes. We review recent studies showing that several pollutants, including phthalates and organotins, interfere with PPAR (peroxisome proliferator-activated receptors) nuclear receptors and may thereby affect metabolic homeostasis. Particular emphasis is given on the mechanisms of action of these compounds. However, unlike what has been suspected, we provide evidence from mouse models suggesting that in utero exposure to the phthalate ester di-ethyl-hexyl-phthalate most likely does not predispose to obesity. Collectively, these studies define a subclass of EDCs that perturb metabolic signaling and that we propose to define as metabolic disruptors.

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Receptor and Nonreceptor-Mediated Organ-Specific Toxicity of Di(2-ethylhexyl)phthalate (DEHP) in Peroxisome Proliferator-Activated Receptorα-Null Mice

Cited by 237 publications

References 19 publications

Peroxisome Proliferator–Activated Receptor α Protects against Glomerulonephritis Induced by Long-Term Exposure to the Plasticizer Di-(2-Ethylhexyl)Phthalate

Peroxisome Proliferator–Activated Receptor α Protects against Glomerulonephritis Induced by Long-Term Exposure to the Plasticizer Di-(2-Ethylhexyl)Phthalate

Liver Hypertrophy

Interference of pollutants with PPARs: endocrine disruption meets metabolism

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