Di(2‐Ethylhexyl) phthalate induces a functional zinc deficiency during pregnancy and teratogenesis that is independent of peroxisome proliferator‐activated receptor‐α

Peters, Jeffrey M.; Taubeneck, Marie W.; Keen, Carl L.; Gonzalez, Frank J.

doi:10.1002/(sici)1096-9926(199711)56:5<311::aid-tera4>3.0.co;2-#

Cited by 83 publications

(32 citation statements)

References 28 publications

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“…Similarly, MEHP, the active metabolite of DEHP, suppresses aromatase expression in a model of reproductive toxicity (13) and induces Fas-dependent apoptosis in testis (10). Much of this toxicity is mediated by PPAR␥ or PPAR␥ together with PPAR␣ (8,9,11,26,27).…”

Section: Discussionmentioning

confidence: 99%

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Environmental and Endogenous Peroxisome Proliferator-Activated Receptor γ Agonists Induce Bone Marrow B Cell Growth Arrest and Apoptosis: Interactions between Mono(2-ethylhexyl)phthalate, 9-cis-Retinoic Acid, and 15-Deoxy-Δ12,14-prostaglandin J2

Schlezinger

Howard

Hurst

et al. 2004

The Journal of Immunology

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The common commercial use of phthalate esters has resulted in significant human exposure to these bioactive compounds. The facts that phthalate ester metabolites, like endogenous PGs, are peroxisome proliferator-activated receptor (PPAR) agonists, and that PPARγ agonists induce lymphocyte apoptosis suggest that phthalate esters are immunosuppressants that could act together with PGs to modulate early B cell development. In this study we examined the effects of a metabolite of one environmental phthalate, mono(2-ethylhexyl)phthalate (MEHP), and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), on developing B cells. MEHP inhibited [3H]thymidine incorporation by primary murine bone marrow B cells and a nontransformed murine pro/pre-B cell line (BU-11). Cotreatment with a retinoid X receptor α ligand, 9-cis-retinoic acid, decreased [3H]thymidine incorporation synergistically, thereby implicating activation of a PPARγ-retinoid X receptor α complex. These results were similar to those obtained with the natural PPARγ ligand 15d-PGJ2. At moderate MEHP concentrations (25 or 100 μM for primary pro-B cells and a pro/pre-B cell line, respectively), inhibition of [3H]thymidine incorporation resulted primarily from apoptosis induction, whereas at lower concentrations, the inhibition probably reflected growth arrest without apoptosis. Cotreatment of bone marrow B cells with 15d-PGJ2 and MEHP significantly enhanced the inhibition of [3H]thymidine incorporation seen with MEHP alone, potentially mimicking exposure in the bone marrow microenvironment where PG concentrations are high. Finally, MEHP- and 15d-PGJ2-induced death does not result from a decrease in NF-κB activation. These data demonstrate that environmental phthalates can cooperate with an endogenous ligand, 15d-PGJ2, to inhibit proliferation of and induce apoptosis in developing bone marrow B cells, potentially via PPARγ activation.

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Section: Discussionmentioning

confidence: 99%

“…MEHP, the active metabolite of DEHP, transcriptionally activates PPAR␣ (15,16). However, PPAR␣ activation alone cannot explain the renal, testicular, or reproductive toxicity or teratogenicity of DEHP, because PPAR␣-null and wild-type mice are equally susceptible to these DEHP-induced toxic effects (8,11,26,27).…”

mentioning

confidence: 99%

Environmental and Endogenous Peroxisome Proliferator-Activated Receptor γ Agonists Induce Bone Marrow B Cell Growth Arrest and Apoptosis: Interactions between Mono(2-ethylhexyl)phthalate, 9-cis-Retinoic Acid, and 15-Deoxy-Δ12,14-prostaglandin J2

Schlezinger

Howard

Hurst

et al. 2004

The Journal of Immunology

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“…Lovekamp-Swan et al suggested that phthalates activate both PPAR and PPAR in cultured rat granulosa cells, resulting in the complete inhibition of aromatase (Lovekamp-Swan et al 2003). However, only a few studies in PPAR -null mice have suggested that some of the effects of DEHP on fertility are mediated by PPAR (Peters et al 1997, Ward et al 1998, Gazouli et al 2002. The administration of DEHP resulted in milder testis lesions and higher testosterone levels in PPAR -null mice than in wild-type mice (Gazouli et al 2002).…”

Section: Ppars -Mediators Of Endocrine Disruptors Of Environmental Ormentioning

confidence: 99%

Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition

Froment¹,

Gizard²,

Defever³

et al. 2006

Journal of Endocrinology

182

132

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“…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%

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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Di(2‐Ethylhexyl) phthalate induces a functional zinc deficiency during pregnancy and teratogenesis that is independent of peroxisome proliferator‐activated receptor‐α

Cited by 83 publications

References 28 publications

Environmental and Endogenous Peroxisome Proliferator-Activated Receptor γ Agonists Induce Bone Marrow B Cell Growth Arrest and Apoptosis: Interactions between Mono(2-ethylhexyl)phthalate, 9-cis-Retinoic Acid, and 15-Deoxy-Δ12,14-prostaglandin J2

Environmental and Endogenous Peroxisome Proliferator-Activated Receptor γ Agonists Induce Bone Marrow B Cell Growth Arrest and Apoptosis: Interactions between Mono(2-ethylhexyl)phthalate, 9-cis-Retinoic Acid, and 15-Deoxy-Δ12,14-prostaglandin J2

Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition

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

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