Metabolism of di (2-ethylhexyl) phthalate (DEHP): comparative study in juvenile and fetal marmosets and rats

Kurata, Yoshimasa; Makinodan, Futoshi; Shimamura, Nobuaki; Katoh, Masanobu

doi:10.2131/jts.37.33

Cited by 31 publications

(26 citation statements)

References 23 publications

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“…In contrast to MBP and MEP, no detectable levels of MEHP conjugation were observed in our in vitro model. These results are consistent with observations in rat DEHP exposures in vivo , in which MEHP has mostly been observed in its free form and is not thought to be conjugated in any significant amount (Keys et al 2000; Kurata et al 2012). …”

Section: Discussionsupporting

confidence: 92%

Phthalate metabolism and kinetics in an in vitro model of testis development

Harris

Wegner

Hong

et al. 2016

Toxicology in Vitro

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We have developed an in vitro model of testis development (3D-TCS) using rat testicular cells overlaid with extracellular matrix. One barrier preventing utilization of in vitro models in toxicity testing is absence of metabolic capability. Another challenge is lack of kinetic data for compounds in vitro. We characterized metabolic capabilities and investigated the kinetics of phthalate male reproductive toxicants in the 3D-TCS. Cells were treated with three phthalate diesters for 2, 8 and 24 hours. Parent compounds and metabolites were measured in cell culture media and cell lysate via mass spectrometry. Levels of monoester metabolites were used as an indication of metabolism of phthalates via lipase activity. Metabolites were detected in all treated cell media and cell lysate samples, with levels ranging from <0.5–14.7% of initial mass of parent compound. Phthalates partitioned between media and lysate in a manner consistent with each compound’s degree of lipophilicity. UDGPT activity was detected in DBP and DEP treated samples. 3D-TCS microarray data indicated gene expression for lipases and CYPP450s. Results indicate that the 3D-TCS is a metabolically active co-culture and that physiochemical properties can provide information about the kinetics of compounds in the 3D-TCS, improving our ability to interpret results from the model.

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Section: Discussionsupporting

confidence: 92%

Phthalate metabolism and kinetics in an in vitro model of testis development

Harris

Wegner

Hong

et al. 2016

Toxicology in Vitro

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“…The exact data of plasma levels of MEHP and its oxidative metabolites and their conjugation status, which are essential issue for assessing the human risk of the reproductive effects of DEHP, will be obtained before long with the plasma samples from the same males and females with the present study (Anderson et al, 2011). In our previous study (Kurata et al, 2012), there were no peaks of free forms of these secondary metabolites in marmoset plasma as suspected; whereas, in rat plasma, highly amount of oxidative metabolites of MEHP existed as free form.…”

Section: Discussionmentioning

confidence: 99%

“…We recently compared the metabolic profile of DEHP in between rats and marmosets (Kurata et al, 2012) using 14 C-DEHP (100 mg/kg). As the results, obvious species differences in urinary excretion of primary and secondary metabolites were demonstrated; in rats, oxidized MEHP metabolites were excreted into urine mostly as unconjugated forms; in contrast, although MEHP and its oxidized metabolites as described above were also detected in the marmoset urine, they were mostly glucuronide conjugated.…”

Section: Discussionmentioning

confidence: 99%

“…In the previous study, male marmosets were treated repeatedly with DEHP by gavage throughout pre-and peri-adolescent period; however, no histological changes were noted in the testes even at 2,500 mg/kg. In addition, we compared the plasma concentration, tissue distribution, and excretion of these metabolites in juvenile and fetus between rats and marmosets (Kurata et al, 2012) to clarify the cause of species differences on the testicular effects, because DEHP is initially hydrolyzed in the intestine, absorbed as MEHP, a primary metabolite, and further oxidized to the secondary metabolites such as COOH-MEHP, OH-MEHP, and oxo-MEHP (Agency for Toxic Substances and Disease Registry [ATSDR], 2002;Koch et al, 2006), and some of these primary and secondary metabolites are believed to be toxicologically active molecules (Gray and Beamand, 1984;Sjöberg et al, 1986;Li et al, 1998;Peck and Albro, 1982;Stroheker et al, 2005;Chauvigne et al, 2009). In the results, obvious species differences were noted in the ratios of glucuronide con-jugate to free form (G/F ratio) of the above metabolites in urine; those of rats and marmosets were 0.13 and 7.14, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Metabolite profiling and identification in human urine after single oral administration of DEHP

Kurata

Shimamura

Katoh³

2012

J. Toxicol. Sci.

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-Di(2-ethylhexyl)phthalate (DEHP) is known to be a reproductive toxicant in male rodents, and its primary or secondary metabolites seem to be causative agents. To identify and quantify urinary metabolites of DEHP in humans, urine samples collected from healthy male and female volunteers following oral administration of deuterium labeled DEHP (d 4 -DEHP) at 3 mg/person were analyzed by a high performance liquid chromatograph/mass spectrometer (LC-MS), and the excretion behavior of orally taken DEHP was evaluated. Mono(2-ethylhexyl)phthalate (MEHP), OH-MEHP, oxo-MEHP, COOH-MEHP, and their glucuronides were identified as metabolites in the male and female urine. The ratios of the conjugate forms in the total urinary metabolites were remarkably high from immediately after administration (0 to 4-hr post-dose), which were approximately 69% to 86% (male) and 80% to 89% (female) until 36-hr post-dose. It was suggested that DEHP taken orally was promptly converted to MEHP and its oxidative metabolites such as OH-MEHP, oxo-MEHP, and COOH-MEHP, and most of these metabolites received the conjugation reaction and were excreted as glucuronides. Remarkable differences from rodents, in which most of these metabolites were excreted as free forms, were demonstrated.

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“…Tissue protein levels were determined using Bradford method (Bradford, 1976). The doses used for arsenic and DEHP were selected based on previous studies (Kurata et al, 2012;Akingbemi et al, 2001;Samuel et al, 2005). The experiment was carried out in accordance with the LAUTECH Department of Biochemistry guidelines for the care and use of laboratory animals.…”

Section: Experimental Designmentioning

confidence: 99%

Combined arsenic and di-(2-ethylhexyl) phthalate exposure elicits responses in brain ATPases different from hepatic and renal activities in rats

Afolabi¹,

Ugbaja²,

Ademuyiwa³

2016

J. Toxicol. Environ. Health Sci.

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Arsenic and di-(2-ethylhexyl) phthalate (DEHP) are environmentally ubiquitous and epidemiologically important toxic agents that millions of people are currently exposed to, worldwide. Although the adverse impact due to exposure to either arsenic or DEHP are documented, the toxicological effects of co-exposure to these agents are largely unknown. In this study, exposure to these chemicals was investigated for their effects on ATPase activities in the brain, liver and kidney of rats. Male Wistar rats were exposed daily to 100 mg L -1 arsenic via drinking water and to 100 mg DEHP kg -1 body weight in corn oil either individually or concurrently for 30 days. Toxicity was assessed by evaluating changes in body and organ weights, as well as, Na + /K + -, Ca 2+ -, Mg 2+ -and total ATPase activities in the brain, liver and kidney. Exposure to either arsenic or DEHP resulted in drastic reduction in activities of the enzymes in the compartments investigated, except in the brain where Na + /K + -and Mg 2+ -ATPases had their activities significantly increased. Also, DEHP displayed no effect on the total ATPase and Ca 2+ATPase in the kidney and brain, respectively. Interestingly, co-exposure to these toxicants significantly stimulated the activities of all these enzymes in the brain. In this compartment, combined treatment resulted in an additive interaction between the toxicants and a potentiation effect of arsenic on DEHP with regards to the Na + /K + -ATPase activity and Ca 2+ -ATPase activity, respectively. Our findings demonstrate tissue specific response to combined arsenic and DEHP exposure in rats with the effect on the brain significantly different from other compartments.

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Metabolism of di (2-ethylhexyl) phthalate (DEHP): comparative study in juvenile and fetal marmosets and rats

Cited by 31 publications

References 23 publications

Phthalate metabolism and kinetics in an in vitro model of testis development

Phthalate metabolism and kinetics in an in vitro model of testis development

Metabolite profiling and identification in human urine after single oral administration of DEHP

Combined arsenic and di-(2-ethylhexyl) phthalate exposure elicits responses in brain ATPases different from hepatic and renal activities in rats

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