Di-(2-ethylhexyl) phthalate: A short-term repeated inhalation toxicity study including fertility assessment

Klimisch, H.-J.; Gamer, Armin; Hellwig, J.; Kaufmann, Wolfgang; Jäckh, Rudolf

doi:10.1016/0278-6915(92)90175-k

Cited by 39 publications

(22 citation statements)

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“…Prolongation of the estrus cycle and decrease in the pregnancy rate in the present toxicity and fertility studies were consid--tion by DEHP. An increase in liver weight (Klimisch et al, 1992) and induction of cytochrome P-450 (Dirven et al, 1990) from administration of DEHP have been reported and the enlarged liver and increase in liver weight in the present study are consistent with above reports.…”

Section: Discussionsupporting

confidence: 93%

Collaborative work on evaluation of ovarian toxicity 10) Two- or four-week repeated dose studies and fertility study of di-(2-ethylhexyl) phthalate (DEHP) in female rats

et al. 2009

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INTRODUCTIONAs part of a collaborative study on toxicity related to female fertility, we performed experiments using di-(2-ethylhexyl) phthalate (DEHP), widely used as a plasticizer of polyvinyl chloride (PVC) and a known peroxisome proliferator (Lake et al., 1987), liver carcinogen (Reddy and Lalwai, 1983) and ovarian toxicant in rodents (Davis et al., 1994). Short-term exposure to DEHP resulted in hypoestrogenic anovulatory cycles and polycystic ovaries in adult rats (Davis et al., 1994). Longterm exposure to DEHP resulted in continuous diestrous stage with reduced serum estradiol, follicle stimulating hormone (FSH), pituitary FSH and luteinizing hormone (LH) (Hirosawa et al., 2006). The active metabolite of DEHP mono-(2-ethylhexyl) phthalate (MEHP) decreased aromatase in rat granulosa cells in vitro (Davis et al., 1994). Because the toxic effects of DEHP on ovaries are thought to be endocrine disorders and an aromatase inhibitor is expected to impact both ovarian morphology and female fertility, we selected DEHP as the test compound for the evaluation of ovarian toxicity.The present study was designed to determine whether 2-or 4-week administration periods for detecting histopathological changes in a repeated-dose toxicity study to compare the potential ovarian toxicity with the female reproductive function in a fertility study. MATERIALS AND METHODS Test articleDEHP was obtained from Kanto Chemical (Tokyo, Japan). Corn oil was purchased from Sigma-Aldrich Japan (Tokyo, Japan) and used as a vehicle. DEHP was ABSTRACT -The main purpose of this collaborative work is to determine the optimal administration period required to detect toxic effects in evaluation of ovarian morphological changes in repeated-dose toxicity studies. To assess the morphological and functional changes induced in the ovaries by di-(2-ethylhexyl) phthalate (DEHP), two repeated-dose toxicity studies (repeated dose for 2 or 4 weeks) of DEHP administrated to female rats at dose levels of 0, 300, 1,000 and 3,000 mg/kg were conducted in collaboration with a female fertility study at the same dosages from 2 weeks prior to mating to Day 7 of pregnancy. Histopathology of the ovaries in both repeated-dose toxicity studies showed vacuolation of stromal cells in the groups receiving 300 mg/kg or more and an increase of large atretic follicles in groups at 1,000 mg/ kg or more. In the 4-week study, a decrease in new corpora lutea was observed in the 3,000 mg/kg group. In the female fertility study, the 3,000 mg/kg group showed prolongation of the mean estrous cycle and irregular estrous cycles. Cesarean section revealed a decrease of pregnancy rate in the 3,000 mg/kg group. No effects on fertility or early embryonic development were found in groups at 1,000 mg/kg or less. -ation of drugs which induce ovarian damage. In conclusion, for a repeated-dose toxicity study, a 2-week

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Section: Discussionsupporting

confidence: 93%

Collaborative work on evaluation of ovarian toxicity 10) Two- or four-week repeated dose studies and fertility study of di-(2-ethylhexyl) phthalate (DEHP) in female rats

et al. 2009

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“…In rats, DEHP administration (3-14 days, 1-2.5 g/Kg/day) causes peroxisomal proliferation and increased activities of several enzymes both in liver and in kidney, and suckling animals appear especially sensitive to lethal and growth retardation eVects (Osumi and Hashimoto 1978;Lake et al 1984;Dostal et al 1987;Sharma et al 1989;Reubsaet et al 1990;Cimini et al 1994;Stefanini et al 1995). In adult rats, moreover, respiratory distress and dose-dependent lethality occur after a single intravenous injection of 200-300 mg/ Kg Tween-solubilised DEHP (Schulz et al 1975), while a 4-week-long aerosol treatment (estimated dose 230 mg/Kg/ day) causes relative lung weight increase, accompanied by foam-cell proliferation and alveolar septa thickening (Klimisch et al 1992). DEHP-induced release of lysosomal enzymes from cultured alveolar macrophages, as well as constriction and oedema of pulmonary vessels in isolated perfused rat heart-lung preparations, has also been reported (Bally et al 1980;Shertzer et al 1982;Labow et al 1990).…”

Section: Introductionmentioning

confidence: 96%

DEHP effects on histology and cell proliferation in lung of newborn rats

Rosicarelli

Stefanini

2008

Histochem Cell Biol

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Di-(2-ethylhexyl)-phthalate (DEHP), the plasticizer employed in the fabrication of polyvinyl chloride, is known to be released by many medical devices, namely endotracheal tubes currently utilised for pulmonary ventilation of pre-term newborns. When experimentally administered, especially to rodents, the phthalate reportedly causes alterations to several tissues, immature animals being even more responsive targets than adult ones. In the present research, female rats were fed with DEHP in the last week of pregnancy and after delivery, and lung of their pups was morphologically and immunohistochemically analysed. We detected significant alveolar simplification (larger but fewer alveoli with decreased septation), with consequent sensible reduction of gas-exchange surface, at several stages of postnatal development, in distal lung parenchyma of DEHP-treated rats. Moreover, the quantification of PCNA-expressing cells demonstrates that in treated pups the proliferation rates of epithelial and mesenchymal cells progressively increased during the first two postnatal weeks, at difference with controls animals, where the highest proliferation levels were reached at postnatal day 7. The obtained results strongly support the hypothesis that DEHP profoundly affects the alveolarization process in mammalian lung.

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“…As far as lung is concerned, in adult rats respiratory distress and dose-dependent lethality occurred after intravenous injection with 200-300 mg/kg Tween-solubilised DEHP (Schulz et al 1975), while aerosol treatment (estimated dose of 230 mg/kg per day, for 4 weeks) caused relative lung weight increase, accompanied by foam-cell proliferation and alveolar septa thickening (Klimisch et al 1992). In vitro, DEHP-induced release of lysosomal enzymes from cultured alveolar macrophages as well as constriction and oedema of pulmonary vessels in isolated perfused rat heart-lung preparation have been reported (Bally et al 1980;Shertzer et al 1982;Labow et al 1990).…”

Section: Introductionmentioning

confidence: 99%

Effects of the plasticiser DEHP on lung of newborn rats: catalase immunocytochemistry and morphometric analysis

Magliozzi

Nardacci

Scarsella

et al. 2003

Histochemistry and Cell Biology

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Experimental administration of di-(2-ethylexyl)-phthalate (DEHP), a plasticiser employed in the fabrication of polyvinyl chloride (PVC), causes increases in lipid metabolising enzymes along with marked peroxisomal proliferation. The effects are found in several mammalian tissues, of which the rodent liver is the most responsive target. Leakage of DEHP from PVC devices is favoured by high temperature and contact with lipid-containing biological fluids. Since preterm babies are currently ventilated through endotracheal PVC tubes, it seemed worthwhile to investigate DEHP effects on immature mammalian lung. In this research, female rats were fed with DEHP in the last week of pregnancy and after delivery, and lungs were excised from 2-day-old pups. At this age, in fact, rat lung histological features closely resemble those found in 24- to 36-week-old human fetuses. In treated animals, morphometric analysis of histological parameters revealed a dramatic decrease in the number of parenchymal airspaces, together with significant increases in their mean size. Moreover, cytochemical detection of the peroxisomal marker catalase revealed an increase in the number of type II pneumocytes. Our findings closely resemble abnormal histological features observed in autoptic lung specimens from children affected with chronic lung diseases.

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Di-(2-ethylhexyl) phthalate: A short-term repeated inhalation toxicity study including fertility assessment

Cited by 39 publications

References 14 publications

Collaborative work on evaluation of ovarian toxicity 10) Two- or four-week repeated dose studies and fertility study of di-(2-ethylhexyl) phthalate (DEHP) in female rats

Collaborative work on evaluation of ovarian toxicity 10) Two- or four-week repeated dose studies and fertility study of di-(2-ethylhexyl) phthalate (DEHP) in female rats

DEHP effects on histology and cell proliferation in lung of newborn rats

Effects of the plasticiser DEHP on lung of newborn rats: catalase immunocytochemistry and morphometric analysis

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