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Submitted on December 5, 2006
Accepted on January 26, 2007
MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.; Division of Biochemistry, Catholic University of Leuven, B-300 Leuven, Belgium.; Institute of Comparative Medicine, University of Glasgow Veterinary School, Glasgow, G61 1QH, UK
* To whom correspondence should be addressed. E-mail: r.sharpe{at}hrsu.mrc.ac.uk.
This study sought to establish if reduced androgen levels/action in the fetal rat testis induced by di(n-butyl) phthalate (DBP) contributes to dysgenetic features, namely reduced Sertoli cell number, occurrence of multinucleated gonocytes (MNG), Leydig cell aggregation. Pregnant rats were administered treatments or co-treatments designed to manipulate testosterone levels (DBP, testosterone propionate; TP) or action (flutamide, DMBA). The aforementioned endpoints were analysed and related to intratesticular testosterone (ITT) levels and peripheral androgen action (anogenital distance; AGD). Dysgenetic features were also evaluated in mice with inactivation of the androgen receptor (tfm or ARKO mice).
Exposure to DBP alone, or combined with flutamide, DMBA or TP, resulted in reduced Sertoli cell number and ITT levels, as did exposure to TP alone; co-administration of DBP + TP caused the most severe reduction in both parameters. A positive correlation between ITT levels and Sertoli cell number was found (r=0.791; p=0.019). Similarly, exposure to DBP alone, or as a co-treatment, significantly increased occurrence of MNG and Leydig cell aggregation, and these were negatively correlated with ITT levels. Exposure to flutamide or DMBA alone had no significant effect on these dysgenetic endpoints. These findings suggest that reduced ITT decreases fetal Sertoli cell numbers, and might be involved in Leydig cell aggregation and MNG. However, of these three endpoints, only Sertoli cell number was affected significantly in ARKO/tfm mice with absent androgen action. Therefore, induction of MNG and Leydig cell aggregation might result from DBP-induced effects other than suppression of ITT levels.
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