This Article Accepted Manuscript (PDF) All Versions of this Article: 135/5/693    most recent REP-07-0460v1 Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gunnarsson, D. Articles by Selstam, G. Search for Related Content PubMed PubMed Citation Articles by Gunnarsson, D. Articles by Selstam, G.

MEHP stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes

D Gunnarsson, Molecular Biology, Umeå University, Umeå, S-901 87, Sweden
P Leffler, Threat Assessment, Swedish Defence Research Agency, Umeå, Sweden
E Ekwurtzel, Molecular Biology, Umeå University, Umeå, Sweden
G Martinsson, Umeå, Sweden
K Liu, Medical Biochemistry and Biophysics, Umeå University, Umeå, United States
G Selstam, Molecular Biology, Umeå University, Umeå, United States

Correspondence: David Gunnarsson, Email: david.gunnarsson{at}molbiol.umu.se

Abstract

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 microM) stimulated basal steroid synthesis in a concentration-dependent manner in immortalized mouse Leydig (MLTC-1) cells. The stimulatory effect was detected also in granulosa (KK-1) tumour 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 microM) up-regulated hormone-sensitive lipase (HSL) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) 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 antisteroidogenic 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 (HPG) axis.