Steroidogenic assessment using ovary culture in cycling rats: Effects of bis (2-diethylhexyl) phthalate on ovarian steroid production

Laskey, John W.; Berman, Ezra

doi:10.1016/0890-6238(93)90006-s

Cited by 59 publications

(40 citation statements)

References 10 publications

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“…However, DEHP-treated rats ovulated if stimulated with an LH-like compound, evidence that suppressed estradiol was the primary toxicity in the ovary (Davis et al 1994a). These results were consistent with another study finding decreased estradiol production in cultures of minced ovaries from DEHP-treated rats in estrus (Laskey and Berman 1993).…”

Section: Pathogenesis Studies In the Female Rodentsupporting

confidence: 83%

Mechanisms of phthalate ester toxicity in the female reproductive system.

Lovekamp-Swan

Davis

2003

Environ Health Perspect

574

288

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Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation.

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Section: Pathogenesis Studies In the Female Rodentsupporting

confidence: 83%

Mechanisms of phthalate ester toxicity in the female reproductive system.

Lovekamp-Swan

Davis

2003

Environ Health Perspect

574

288

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“…The 1st incubation hour was basal (unstimulated), the 2nd hour was stimulated with human chorionic gonadotropin (hCG), and the 3rd hour was stimulated with both hCG and substrate pregnenolone. The culture of whole rat ovary proved to be better for steroid hormone assay than serum-hormone assays for characterizing steroid production in the normal ovary, as well as for confidently detecting alteration(s) and identifying the general site(s) of altered steroidogenesis (Berman et al 1990(Berman et al , 1991Laskey et al 1991aLaskey et al , 1991bLaskey et al , 1995Berman and Laskey 1993;Laskey and Berman 1993).…”

Section: Culture Conditions and Samplingmentioning

confidence: 97%

“…In the 1990s Laskey and Berman introduced whole-ovary culture as a rapid and convenient in-vitro assay for steroidogenic activity following in-vivo toxicant exposure (Berman et al 1990(Berman et al , 1991Laskey et al 1991aLaskey et al , 1991b. Since then, various chemicals suspected of interfering with normal steroidogenesis in non-pregnant (cycling) and pregnant rats, such as dibutylphthalate, diethylhexyl phthalate, ethane dimethane sulfonate, epostane, methoxychlor, aminoglutethamide phosphate, and fungicide fenarimol, have been tested by Laskey, Berman and coworkers using whole-ovary culture (Berman et al 1990(Berman et al , 1991Laskey et al 1991aLaskey et al , 1991bLaskey et al , 1995Cummings and Laskey 1993;Berman and Laskey 1993;Laskey and Berman 1993).…”

mentioning

confidence: 98%

Assessment of steroid disruption using cultures of whole ovary and/or placenta in rat and in human placental tissue

Piasek

Laskey

Kostial

et al. 2002

International Archives of Occupational and Environmental Health

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“…used (Laskey & Berman 1993, Davis et al 1994a. In a study on human exposure, the calculated intake of DEHP by women reached a maximum of 15 mg/kg per day (McKee et al 2004).…”

Section: Discussionmentioning

confidence: 99%

The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats

Svechnikova

Svechnikov

Söder

2007

Journal of Endocrinology

118

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Phthalate esters are known to exert harmful effects on mammalian reproduction and fertility, but their potential adverse effects on the hormonal functions of the ovary have not yet been elucidated in detail. Here, we investigated the effects of di-(2-ethylhexyl) phthalate (DEHP) on the hypothalamic-pituitary-gonadal axis of young developing female rats, as well as on ex vivo steroidogenesis by granulosa cells (GCs) and secretion of LH by gonadotropes. Exposure of 20-day-old female rats to 500 mg DEHP by oral gavage once daily for 10 days reduced their serum levels of progesterone and estradiol, while tending to enhance levels of LH. Furthermore, primary cultures of GCs isolated from these rats exhibited an attenuated capacity to produce progesterone in response to stimulation by LH and FSH, as well as a lower degree of transport of endogenous cholesterol into mitochondria. Moreover, the ability of primary cultures of pituitary cells isolated from DEHPtreated rats to produce and secrete LH in response to GnRH was significantly enhanced. In addition, 2-ethylhexanoic acid, a metabolite of DEHP, significantly potentiated GnRH-stimulated production of LH by cultures of pituitary cells isolated from untreated 20-day-old female rats. Together, these data indicate that DEHP exerts dual effects on the pituitary-gonadal axis, stimulating the hormonal function of the pituitary and, at the same time, by inhibiting steroidogenesis by GCs.

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Steroidogenic assessment using ovary culture in cycling rats: Effects of bis (2-diethylhexyl) phthalate on ovarian steroid production

Cited by 59 publications

References 10 publications

Mechanisms of phthalate ester toxicity in the female reproductive system.

Mechanisms of phthalate ester toxicity in the female reproductive system.

Assessment of steroid disruption using cultures of whole ovary and/or placenta in rat and in human placental tissue

The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats

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