Comparison of oxidative stress and changes of xenobiotic metabolizing enzymes induced by phthalates in rats

Seo, Kyung Won; Kim, Kyu Bong; Kim, Yun Jung; Choi, Ju Young; Lee, Kyung Tae; Choi, Kwang Sik

doi:10.1016/j.fct.2003.08.010

Cited by 98 publications

(53 citation statements)

References 30 publications

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“…The glutathione adducts produced in the detoxification process have an increased solubility in water and are subsequently enzymatically degraded to mercapturates and excreted. Recent studies have shown that several phthalates caused a significant decrease in the GST activity in rats and hamsters (57)(58)(59). This inhibitory effect of phthalates in the GST activity permits the modulation of the biological response and toxicity of chemicals that are detoxified or metabolized via GST.…”

Section: Fig 4 Representative 2-de Cy Dye-stained Protein Gels Withmentioning

confidence: 99%

Identification of Proteomic Signatures of Exposure to Marine Pollutants in Mussels (Mytilus edulis)

Apraiz

Cristóbal

2006

Molecular & Cellular Proteomics

163

121

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Bivalves and especially mussels are very good indicators of marine and estuarine pollution, and so they have been widely used in biomonitoring programs all around the world. However, traditional single parameter biomarkers face the problem of high sensitivity to biotic and abiotic factors. In our study, digestive gland peroxisome-enriched fractions of Mytilus edulis (L., 1758) were analyzed by DIGE and MS. We identified several proteomic signatures associated with the exposure to several marine pollutants (diallyl phthalate, PBDE-47, and bisphenol-A). Animals collected from North Atlantic Sea were exposed to the contaminants independently under controlled laboratory conditions. One hundred and eleven spots showed a significant increase or decrease in protein abundance in the two-dimensional electrophoresis maps from the groups exposed to pollutants. We obtained a unique protein expression signature of exposure to each of those chemical compounds. Moreover a set of proteins composed a proteomic signature in common to the three independent exposures. It is remarkable that the principal component analysis of these spots showed a discernible separation between groups, and so did the hierarchical clustering into four classes. The 14 proteins identified by MS participate in ␣-and ␤-oxidation pathways, xenobiotic and amino acid metabolism, cell signaling, oxyradical metabolism, peroxisomal assembly, respiration, and the cytoskeleton. Our results suggest that proteomic signatures could become a valuable tool to monitor the presence of pollutants in field experiments where a mixture of pollutants is often present. Further studies on the identified proteins could provide crucial information to understand possible mechanisms of toxicity of single xenobiotics or mixtures of them in marine ecosystems.

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Section: Fig 4 Representative 2-de Cy Dye-stained Protein Gels Withmentioning

confidence: 99%

Identification of Proteomic Signatures of Exposure to Marine Pollutants in Mussels (Mytilus edulis)

Apraiz

Cristóbal

2006

Molecular & Cellular Proteomics

163

121

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“…Because some studies have suggested that DEHP-induced elevation of oxidative stress contributes to hepatotoxicity and testicular toxicity (23)(24)(25), the influence of oxidative stress in DEHP-induced glomerulonephritis was examined. Immunoblot analysis showed that total amounts of 4-HNE-modified proteins, a lipid peroxidation marker, were increased markedly and dosage dependently in glomeruli of DEHP-exposed PPAR␣-null mice at 22 mo but increased only mildly in exposed wild-type mice ( Figure 5A).…”

Section: Dehp Elevates Oxidative Stress In Glomerulimentioning

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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“…However, because these chemicals do not show any mutagenic potential in genotoxicity tests, they are regarded as non-genotoxic hepatocarcinogens. On the contrary, it has been speculated that PPARα agonists markedly induce H 2 O 2 -generating enzymes, such as acyl-CoA oxidase and cytochrome p450 4A, resulting in increased levels of hydrogen peroxide, a reactive oxygen species (ROS), leading to lipid peroxidation and oxidative DNA damage (Yeldandi et al, 2000;Seo et al, 2004). Such an oxidative stress induced by PPARα agonists is considered to be an indirect mechanism involved in hepatocarcinogenesis (Reddy and Rao, 1989;Klaunig and Kamendulis, 2004;Seo et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Twenty-six-week oral toxicity of diheptyl phthalate with special emphasis on its induction of liver proliferative lesions in male F344 rats

Nakane¹,

Kunieda²,

Shimizu³

et al. 2012

J. Toxicol. Sci.

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(Mannaerts et al., 1993). PPARs are members of the steroid hormone receptor superfamily, and three related isotypes, specifically PPARα, PPARβ and PPARγ, have been identified (Desvergne and Wahli, 1999). Based on target gene expression patterns, PPARα appears to have critical roles in the regulation of fatty acid metabolism, including fatty acid β-oxidation, apolipoproteins, and fatty acid transport proteins (Lee et al., 1995;Auwerx et al., 1996;Aoyama et al., 1998;Peters et al., 1997;Ren et al., 1997;Martin et al., 1997). Additionally, chronic exposure to numerous PPARα agonists has been reported to increase the incidence of hepatocellular tumors in rodents ABSTRACT -The 26-week oral toxicity of diheptyl phthalate (DHP), a peroxisome proliferator-activated receptor α (PPARα) agonist, with special emphasis on the potential induction of hepatocellular proliferative lesions was investigated in this study. DHP was administered to male F344 rats via gavage at 0 (control), 1,000 or 2,000 mg/kg/day for 26 weeks. Body weight gain was significantly lower, whereas food and water consumption was significantly higher in DHP-treated rats compared with controls. DHPtreated rats exhibited decreases in blood triglyceride, total cholesterol, phospholipid and glucose levels, which were likely related to biological effects of the PPARα agonist. Absolute and relative organ weights of the livers with pale brown discoloration and dark brown spots significantly increased in DHP-treated rats. Histopathological examinations revealed remarkable diffuse hypertrophy of hepatocytes with groundglass appearance, intracytoplasmic inclusion bodies and/or vacuolation in the DHP-treated groups. These findings were associated with increases in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyltranspeptidase. The number and area of glutathione S-transferase placental form positive foci, a marker of hepatocellular preneoplastic lesions in rats, significantly increased in DHP-treated groups. Additionally, proliferating cell nuclear antigen positive liver cell counts in DHPtreated groups were significantly higher than those of the controls. Testicular alterations were not detected histopathologically, whereas absolute and relative prostate weights significantly decreased at both doses. These results indicate that DHP induces liver pre-neoplastic foci, and suggest the possibility that DHP is a possible genotoxic carcinogen in the liver of rats.

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Comparison of oxidative stress and changes of xenobiotic metabolizing enzymes induced by phthalates in rats

Cited by 98 publications

References 30 publications

Identification of Proteomic Signatures of Exposure to Marine Pollutants in Mussels (Mytilus edulis)

Identification of Proteomic Signatures of Exposure to Marine Pollutants in Mussels (Mytilus edulis)

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

Twenty-six-week oral toxicity of diheptyl phthalate with special emphasis on its induction of liver proliferative lesions in male F344 rats

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