Phthalate Esters, Cystic Kidney Disease in Animals and Possible Effects on Human Health: A Review

Woodward, K.N.

doi:10.1177/096032719000900607

Cited by 25 publications

(16 citation statements)

References 37 publications

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“…Alternatively, it is pos-sible that other receptor subtypes (PPARG or y) may play a role in the observed delayed kidney toxicity or the high dose of DEHP may modify the pharmacokinetics of DEHP in these mice. The renal tubular lesions including cystic tubular disease in (+/+) and (-/-) mice resembled those seen in renal dialysis patients (25).…”

Section: Discussionmentioning

confidence: 67%

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

Ward¹,

Peters

Perella³

et al. 1998

Toxicol Pathol

237

154

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The peroxisome proliferator-activated reccptora (PPARa) is the mediator of the biological effects of pcroxisome proliferators through control of gene transcription. To determine if the toxic effects of di(2-ethylhexy1)phthalate (DEHP) are mediated by PPARa, we examined its effect in PPARa-null micc. Male Sv1129 mice. PPARa-null (-/-) or wild-typc (+I+) were fed nd libirirrn either a control diet or one containing 12.000 ppm DEHP for up to 24 wk. Significant body weight loss and high mortality was observcd in (+/+) mice fed DEHP. By 16 wk, all DEHP-fed (+I+) mice had died of cystic renal tubular disease. In contrast, the (-/-) mice fed DEHP had no changes in body weight until later in the study nor increased mortality. Histologically, (+/+) mice fed DEHP had typical toxic lesions in liver, kidney, and testis while (-/-) mice fed DEHP had no toxic liver lcsions but did show cvidence of toxicity in kidney and testis after 4-8 wk of feeding, which progressed into moderate lesions by 24 wk. Analysis of hepatic and renal mRNAs showed a typical pleiotropic response in gene expression in the DEHP-fed (+/+) mice that was absent in the DEHP-fed (-1 -) mice. These results provide evidence that PPARa mediates the subacute-chronic toxicity of DEHP in liver, kidney, and testis. However, because (-/-) mice did develop toxic lesions in kidney and testis. DEHP can also act through PPARa-independcnt pathways in mediating renal and testicular toxicity. Knockout mice; peroxisomal proliferator; liver; peroxisomal proliferator activated receptor; di(2-ethylhexy1)phthalate (DEHP); kidney; cystic kidneys Keywords.

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Section: Discussionmentioning

confidence: 67%

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

Ward¹,

Peters

Perella³

et al. 1998

Toxicol Pathol

237

154

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“…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)(4)(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).…”

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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“…In addition, histological damage in testis, kidney and liver during pregnancy and suckling [63], cryptorchidism after prenatal exposition [64] and persistent thyroid hyperactivity [65] were observed. Then, polycystic kidney disease and a decrease in kidney function [66,67] as well as a dose-dependent decrease of cell viability in kidney epithelial cells [68], hypotension and cardiac arrest [69], decrease in the concentration of vitamin E in liver and testis [70] and finally peroxisome proliferation in liver, kidney and brain [71][72][73][74] were also reported. …”

Section: Evidence Of Toxicity In Experimental Animalsmentioning

confidence: 99%

“…Similarly, polycystic kidney disease in long-term hemodialysis patients and renal cysts in DEHPtreated rodents have been observed since the end of the 1970s. Therefore, although a causal relationship between the two phenomena was not found, DEHP long-term exposure is likely to result in renal cysts both in animals and in humans [66,67]. Finally, it is more complex to establish if testicular and ovarian damage and consequently reproductive toxicity, that are rodent specific, might also be present in humans.…”

Section: Is Dehp Safe?mentioning

confidence: 99%

Potential Hazards of Exposure to Di-(2-Ethylhexyl)-Phthalate in Babies

Latini

2000

Neonatology

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Many plastic items are made of polyvinylchloride (PVC) blended with plasticizers. The most frequently used plasticizer is di-(2-ethylhexyl)-phthalate (DEHP). DEHP migrates at a constant rate from plastics to the environment: it has been detected in water, soil and food and is therefore considered as a widespread environmental contaminant. Over the past several years, a number of publications concerning toxic effects of DEHP on animals and humans have been reported. Although DEHP is suggested to be of low acute toxicity, long-term exposure, especially in human beings at risk such as pregnant women and children, requires more in-depth studies. If DEHP toxicity in humans were to be confirmed, it would be advisable in the future to replace current PVC plasticizers, especially if they come into contact with babies, with better-quality materials.

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Phthalate Esters, Cystic Kidney Disease in Animals and Possible Effects on Human Health: A Review

Cited by 25 publications

References 37 publications

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

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

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

Potential Hazards of Exposure to Di-(2-Ethylhexyl)-Phthalate in Babies

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