Inhibition of FSH-stimulated cAMP accumulation and progesterone production by mono(2-ethylhexyl) phthalate in rat granulosa cell cultures

Treinen, Kimberley A.; Dodson, William C.; Heindel, Jerrold J.

doi:10.1016/0041-008x(90)90252-p

Cited by 67 publications

(46 citation statements)

References 19 publications

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“…A number of possible mechanisms have been proposed to explain phthalate toxicity observed in the testis, including suppression of FSH-mediated cAMP signaling [9,17,18], alterations in the Sertoli cell cytoskeleton [19,20], and induction of Fas/FasL signaling in the initiation of germ cell apoptosis [21,22]. We previously demonstrated that MEHP negatively affects distinct junctional complexes between Sertoli cells and germ cells, and consequently, MEHP exposure results in a significant loss of germ cells in the seminiferous tubule [2].…”

Section: Discussionmentioning

confidence: 97%

Transcriptional Suppression of Sertoli Cell Timp2 in Rodents Following Mono-(2-ethylhexyl) Phthalate Exposure Is Regulated by CEBPA and MYC1

Yao

Lin

Richburg

2011

Biology of Reproduction

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Our previous studies showed that the prototypical testicular toxic phthalate monoester, mono-(2-ethylhexyl) phthalate (MEHP), suppresses Sertoli cell TIMP2 levels and allows for the activation of MMP2 in seminiferous epithelium. Activation of MMP2 is important for triggering germ cell apoptosis and instigating germ cell detachment from Sertoli cells. These novel findings led us to examine the transcriptional regulation of the Timp2 gene that accounts for the decrease in Sertoli cell TIMP2 levels following MEHP exposure. Sequential deletion of the Timp2 5'-upstream activating sequence (1200 bp) was used to survey transcriptional activation in the Timp2 promoter region in response to MEHP. Results indicate that under control conditions in rat Sertoli cells, CCAAT enhancer-binding protein alpha (CEBPA) acts as a transactivator to initiate Timp2 gene transcription, and its action is deactivated by exposure to MEHP. By contrast, MYC protein acts as an inhibitor of Timp2 gene transcription, and its activity is increased after MEHP treatment. Addition of follicle-stimulating hormone (FSH) to cells causes translocation of CEBPA into the Sertoli cell nucleus and rescues MEHP-suppressed TIMP2 levels. Down-regulation of TIMP2 expression by MEHP exposure is blocked by forskolin (a cAMP-elevating agent), suggesting that the decrease in Sertoli cell TIMP2 expression following MEHP exposure is cAMP-dependent. Taken together, these data indicate that MEHP both disrupts the FSH-stimulated cAMP signaling pathway and activates the inhibitory signaling mediated by MYC protein, to ultimately account for the cellular mechanism underlying the decreased expression of TIMP2 in Sertoli cells.

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Section: Discussionmentioning

confidence: 97%

Transcriptional Suppression of Sertoli Cell Timp2 in Rodents Following Mono-(2-ethylhexyl) Phthalate Exposure Is Regulated by CEBPA and MYC1

Yao

Lin

Richburg

2011

Biology of Reproduction

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“…In rat ovarian granulosa cell cultures, MEHP (100 µM) inhibited FSH-stimulated cAMP and progesterone production (Treinen et al 1990). The decrease in progesterone was prevented by stimulators of cAMP or by pregnenolone, the precursor of progesterone.…”

Section: Mehp Decreases Estradiol and Aromatase In Granulosa Cellsmentioning

confidence: 99%

Mechanisms of phthalate ester toxicity in the female reproductive system.

Lovekamp-Swan

Davis

2003

Environ Health Perspect

576

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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“…GCs were isolated from immature rat ovaries, as described previously (Treinen et al 1990). In brief, after trimming away the surrounding tissue, the ovaries were placed in 3 ml DMEM:F-12 (1:1) medium supplemented with penicillin (100 U/ml), streptomycin (100 mg/ml), and 0 .…”

Section: Isolation and Primary Culture Of Gcsmentioning

confidence: 99%

“…In primary cultures of rat granulosa cells (GCs), stimulation of adenylate cyclase and progesterone synthesis by folliclesimulating hormone (FSH) is inhibited by MEHP (Treinen et al 1990). Moreover, this compound suppresses estradiol production by the same cells by a mechanism that is independent of the elevation in cAMP levels caused by FSH (Davis et al 1994b).…”

Section: Introductionmentioning

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

119

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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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Inhibition of FSH-stimulated cAMP accumulation and progesterone production by mono(2-ethylhexyl) phthalate in rat granulosa cell cultures

Cited by 67 publications

References 19 publications

Transcriptional Suppression of Sertoli Cell Timp2 in Rodents Following Mono-(2-ethylhexyl) Phthalate Exposure Is Regulated by CEBPA and MYC1

Transcriptional Suppression of Sertoli Cell Timp2 in Rodents Following Mono-(2-ethylhexyl) Phthalate Exposure Is Regulated by CEBPA and MYC1

Mechanisms of phthalate ester toxicity in the female reproductive system.

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

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