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Differential effects of cadmium on the gene expression of seven-transmembrane-spanning receptors and GAPDH in the rat testis.
Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology). (Selstam)
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Occupational and Enviromental Medicine.
Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine). (Selstam)
2007 (English)In: Toxicology Letters, ISSN 0378-4274, Vol. 168, no 1, 51-7 p.Article in journal (Refereed) Published
Abstract [en]

Cadmium (Cd) is a widely spread toxicant with endocrine disrupting properties. Under experimental conditions it suppresses sex steroid synthesis in the male as well as the female. Testicular steroidogenesis is primarily regulated by gonadotropins, but is also influenced by catecholamines. We have previously shown that Cd exposure affects rat testosterone synthesis by down-regulating luteinizing hormone (LH) receptor mRNA expression. In this study, rats were given 10 micromol/kg Cd subcutaneously and sacrificed 0.48-144 h later. We investigated the effects of Cd on testicular gene expression of two adrenergic receptors. In addition, mRNA levels of the androgen-regulated house keeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were measured. In contrast to the suppressive influence on LH receptor expression Cd lacked effect on the expression of alpha(1A)- and beta(2)-adrenergic receptors. GAPDH gene expression, on the other hand, was up-regulated 1.6-fold after exposure to 10 micromol/kg Cd. These data suggest that the influence of Cd on testicular gene expression involves a specific effect on the LH receptor and not a general effect on seven-transmembrane-spanning receptors. Also, data indicate that the increased expression of GAPDH may be secondary to Cd-induced testosterone deprivation, suggesting future studies of androgen-regulated genes in the toxicity of Cd.

Place, publisher, year, edition, pages
2007. Vol. 168, no 1, 51-7 p.
Keyword [en]
Animals, Cadmium/*toxicity, Gene Expression/*drug effects, Glyceraldehyde-3-Phosphate Dehydrogenases/*genetics, Male, RNA; Messenger/metabolism, Rats, Rats; Sprague-Dawley, Receptors; Adrenergic; alpha-1/genetics, Receptors; Adrenergic; beta-2/genetics, Testis/*drug effects/metabolism
URN: urn:nbn:se:umu:diva-16509DOI: 10.1016/j.toxlet.2006.10.015PubMedID: 17123754OAI: diva2:156182
Available from: 2007-10-04 Created: 2007-10-04 Last updated: 2010-01-04Bibliographically 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.
Endocrine disruptors, reproductive toxicology, cadmium, phthalates, DEHP, MEHP, phytoestrogens, steroidogenesis, testosterone, Leydig cell
National Category
Biochemistry and Molecular Biology
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)
Available from: 2008-10-09 Created: 2008-10-09 Last updated: 2010-04-06Bibliographically approved

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Gunnarsson, DavidNordberg, GunnarSelstam, Gunnar
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