Dual activation of PPARα and PPARγ by mono-(2-ethylhexyl) phthalate in rat ovarian granulosa cells

Lovekamp-Swan, Tara; Jetten, Anton M.; Davis, Barbara J.

doi:10.1016/s0303-7207(02)00423-9

Cited by 180 publications

(86 citation statements)

References 32 publications

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“…Of the three known isoforms, PPARa, PPARb, and PPARg, MEHP has been found to activate the a and g isoforms (Venkata et al 2006). Both these isoforms are expressed in Leydig as well as granulosa cells, and MEHP-induced activation of these transcription factors may explain the increased HSL and HMG-CoA reductase expression found in this study (Schultz et al 1999, Lovekamp-Swan et al 2003, Borch et al 2006. The PPARa activation has been related to increased HMG-CoA reductase mRNA expression and cholesterogenesis, whereas the activation of PPARg increases the expression of HSL (Le Jossic- Corcos et al 2004, Feige et al 2007.…”

Section: Discussionmentioning

confidence: 60%

“…In favor of this hypothesis, known PPARg ligands increase granulosa cell progesterone synthesis by a mechanism described to be independent of p450scc and 3bHSD (Froment et al 2003). The effects of MEHP exposure on the liver and ovary have been attributed to PPAR activation (Lovekamp-Swan et al 2003, but the role of PPAR signaling in testicular toxicity is not that clear.…”

Section: Discussionmentioning

confidence: 99%

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Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

Gunnarsson

Leffler²,

Ekwurtzel³

et al. 2008

Reproduction

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Phthalates are widely used as plasticizers in a number of daily-life products. In this study, we investigated the influence of mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of the frequently used plasticizer di-(2-ethylhexyl) phthalate (DEHP), on gonadal steroidogenesis in vitro. MEHP (25-100 mM) stimulated basal steroid synthesis in a concentration-dependent manner in immortalized mouse Leydig tumor cells (MLTC-1). The stimulatory effect was also detected in KK-1 granulosa tumor cells. MEHP exposure did not influence cAMP or StAR protein levels and induced a gene expression profile of key steroidogenic proteins different from the one induced by human chorionic gonadotropin (hCG). Simultaneous treatment with MEHP and a p450scc inhibitor (aminoglutethimide) indicated that MEHP exerts its main stimulatory effect prior to pregnenolone formation. MEHP (10-100 mM) up-regulated hormone-sensitive lipase and 3-hydroxy-3-methylglutaryl coenzyme A reductase, suggesting that MEHP increases the amount of cholesterol available for steroidogenesis. Our data suggest that MEHP, besides its known inhibitory effect on hCG action, can directly stimulate gonadal steroidogenesis in both sexes through a cAMP-and StAR-independent mechanism. The anti-steroidogenic effect of DEHP has been proposed to cause developmental disorders such as hypospadias and cryptorchidism, whereas a stimulation of steroid synthesis may prematurely initiate the onset of puberty and theoretically affect the hypothalamic-pituitary-gonadal axis. Reproduction (2008) 135 693-703

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

Gunnarsson

Leffler²,

Ekwurtzel³

et al. 2008

Reproduction

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“…Furthermore, decrease in pituitary gland weight is considered to be from DEHP-or MEHP (active suppressing aromatase (Lovekamp-Swan et al, 2003). A: Stromal cells in control group in 4-week study.…”

Section: Discussionmentioning

confidence: 99%

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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“…PPAR and PPAR are responsive to DEHP in vitro and are translocated to the nucleus in primary Sertoli cells after the incubation of these cells with phthalate esters (Dufour et al 2003, Bhattacharya et al 2005. 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.…”

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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Dual activation of PPARα and PPARγ by mono-(2-ethylhexyl) phthalate in rat ovarian granulosa cells

Cited by 180 publications

References 32 publications

Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

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

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

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