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Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes
Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
Umeå University, Faculty of Science and Technology, European CBRNE Center.
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2008 (English)In: Reproduction, ISSN 1470-1626, E-ISSN 1476-3990, Vol. 135, no 5, 693-703 p.Article in journal (Refereed) Published
Abstract [en]

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 µM) 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 µM) 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.

Place, publisher, year, edition, pages
2008. Vol. 135, no 5, 693-703 p.
Identifiers
URN: urn:nbn:se:umu:diva-3527DOI: 10.1530/REP-07-0460OAI: oai:DiVA.org:umu-3527DiVA: diva2:142273
Available from: 2008-10-09 Created: 2008-10-09 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Reproductive toxicology of endocrine disruptors: effects of cadmium, phthalates and phytoestrogens on testicular steroidogenesis
Open this publication in new window or tab >>Reproductive toxicology of endocrine disruptors: effects of cadmium, phthalates and phytoestrogens on testicular steroidogenesis
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A number of investigations during the last two decades describe adverse trends in male reproductive health, which have been proposed to be caused by environmental factors with endocrine disrupting properties. In contrast to many other toxicants, endocrine disruptors often do not show linear dose-response relationships typical of those found in traditional toxicological studies. For many compounds, low-dose exposure causes effects opposite to the ones seen after high-dose exposure. In addition, the timing of exposure has been found to be critical. Hence, to correctly assess the impact of endocrine disruptors on reproductive health requires in-depth knowledge of their mechanisms of action.

This thesis aimed at identifying the mechanisms underlying the effects of cadmium (Cd), phthalates and phytoestrogens on testicular steroidogenesis. For this purpose, in vitro as well as in vivo models were used. Cd was found to inhibit testosterone synthesis in vivo by down-regulating LH receptor gene expression and reducing the testicular levels of cAMP and StAR protein. In addition, Cd caused a pronounced increase in testicular prostaglandin F (PGF), suggesting that Cd exerts its suppressive effect on steroidogenesis also by inducing the inhibitory PKC pathway. Pre-treatment with zinc (Zn) protected completely against Cd-induced effects on testosterone and PGF. Furthermore, we observed that Cd exposure increased glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA expression in the testis. GAPDH is a potent coactivator of androgen receptor-mediated transcription and the up-regulation found in our study is probably a compensatory response to reduced testosterone concentrations. This finding is interesting since GAPDH has been proposed to have an important role in the regulation of apoptosis as well as sperm motility. We discovered that mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of the frequently used phthalate di-(2-ethylhexyl) phthalate (DEHP), stimulates Leydig cell steroidogenesis in vitro, by a cAMP- and StAR-independent mechanism. MEHP exposure caused a similar effect in granulosa cells. Gene expression analysis revealed that MEHP is likely to stimulate steroidogenesis by increasing the amount of cholesterol available for steroid synthesis. In the last investigation, we examined the effects of low-dose phytoestrogen exposure on testosterone synthesis during puberty in male goats. Isoflavones present in clover increased plasma concentrations of testosterone and free as well as total triiodothyronine (T3). T3 has previously been shown to induce testosterone synthesis and it is possible that an elevated T3 secretion underlies the increased plasma testosterone levels.

Reduced fertility and reproductive tract malformations affect both the individual and the society. Hence, a sound knowledge of reproductive toxicants is of crucial importance. The findings presented in this thesis provide new insights into the reproductive toxicology of endocrine disruptors and may be valuable for risk assessment purposes.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi (Teknisk-naturvetenskaplig fakultet), 2008. 90 p.
Keyword
Endocrine disruptors, reproductive toxicology, cadmium, phthalates, DEHP, MEHP, phytoestrogens, steroidogenesis, testosterone, Leydig cell
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-1876 (URN)978-91-7264-631-5 (ISBN)
Public defence
2008-10-31, Major Groove, Building 6L, Department of Molecular Biology, Umeå University S-901 87, Umeå, Sweden, 10:00 (English)
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Available from: 2008-10-09 Created: 2008-10-09 Last updated: 2010-04-06Bibliographically approved

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Publisher's full texthttp://dx.doi.org/10.1530/REP-07-0460

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