The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats.
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 DEHP-treated 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.
Svechnikova
I
I
Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute and University Hospital, Q2:08, 171 76 Stockholm, Sweden. irina.svechnikova@ki.se
Svechnikov
K
K
Söder
O
O
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002208:Caproates / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects; D007986:Luteinizing Hormone / Q000096:biosynthesis / Q000097:blood / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D010053:Ovary / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects; D010968:Plasticizers / Q000633:toxicity*; D011374:Progesterone / Q000096:biosynthesis* / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation; D013268:Stimulation, Chemical
D002208:Caproates; D010968:Plasticizers; C040668:2-ethylhexanoic acid; D013196:Dihydrotestosterone; D000616:Aminoglutethimide; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D002784:Cholesterol; D004051:Diethylhexyl Phthalate; D015096:3-Hydroxysteroid Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme; C009954:trilostane