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Cadmium-induced decrement of the LH receptor expression and cAMP levels in the testis of rats
Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
Umeå University, Faculty of Medicine, Clinical Sciences.
Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
2003 (English)In: Toxicology, ISSN 0300-483X, Vol. 183, no (1-3), 57-63 p.Article in journal (Refereed) Published
Abstract [en]

Cadmium (Cd) is a widespread environmental pollutant, characterized by its ability to affect various organs. Adverse effect of Cd on the testis including decreased testosterone production are well-known phenomena, but the cellular events explaining these effects have not yet been established. In the present study the initial steps of gonadotropin mediated testosterone biosynthesis were examined in vivo in rats, in relation to Cd dose and time after injection. In the dose–response experiment Male Sprague–Dawley rats received a single subcutaneous (sc) injection of CdCl2 (1, 5 or 10 μmol/kg body weight) and were sacrificed 48 h after injection. A statistically significant decrease in luteinizing hormone (LH) receptor mRNA level in the testicular tissue was demonstrated at the highest dose (10 μmol/kg). In the temporal–response experiment rats were given 10 μmol/kg of CdCl2 sc and sacrificed 0.48, 4.8, 48 or 144 h after injection. LH receptor mRNA levels as well as cyclic adenosine monophosphate (cAMP) levels were found to be significantly lowered at 48 and 144 h. These observations of the mechanisms whereby Cd exerts its effect on the initial steps of testosterone biosynthesis are the first from in vivo experiments.

Place, publisher, year, edition, pages
2003. Vol. 183, no (1-3), 57-63 p.
Keyword [en]
Cadmium; Luteinizing hormone receptor; Cyclic adenosine monophosphate system; Steroidogenesis; Rat; Testis
URN: urn:nbn:se:umu:diva-3524DOI: 10.1016/S0300-483X(02)00440-7OAI: diva2:142270
Available from: 2008-10-09 Created: 2008-10-09 Last updated: 2009-06-23Bibliographically 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, GunnarLundgren, PerSelstam, Gunnar
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