Role of androgens in fetal testis development and dysgenesis.
This study sought to establish whether 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), and Leydig cell aggregation. Pregnant rats were administered treatments or cotreatments designed to manipulate testosterone levels [DBP, testosterone propionate (TP)] or action [flutamide, 7,12-dimethyl-benz[a]anthracene (DMBA)]. The aforementioned end points were analyzed and related to intratesticular testosterone (ITT) levels and peripheral androgen action (anogenital distance). Dysgenetic features were also evaluated in mice with inactivation of the androgen receptor (testicular feminized 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; coadministration 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 cotreatment, 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 end points. 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 end points, only Sertoli cell number was affected significantly in ARKO/testicular feminized 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.
Scott
Hayley M
HM
Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Hutchison
Gary R
GR
Mahood
I Kim
IK
Hallmark
Nina
N
Welsh
Michelle
M
De Gendt
Karel
K
Verhoeven
Guido
G
O'Shaughnessy
Peter
P
Sharpe
Richard M
RM
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D001835:Body Weight; D002273:Carcinogens / Q000494:pharmacology; D003993:Dibutyl Phthalate / Q000494:pharmacology; D005260:Female; D005262:Feminization / Q000473:pathology / Q000503:physiopathology; D005485:Flutamide / Q000494:pharmacology; D015726:Giant Cells / Q000473:pathology; D006059:Gonadal Dysgenesis / Q000473:pathology* / Q000503:physiopathology*; D007985:Leydig Cells / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000235:genetics; D012708:Sertoli Cells / Q000473:pathology; D013737:Testis / Q000002:abnormalities* / Q000473:pathology; D013739:Testosterone / Q000172:deficiency* / Q000502:physiology*
D000726:Androgen Antagonists; D002273:Carcinogens; D011944:Receptors, Androgen; D003993:Dibutyl Phthalate; D013739:Testosterone; D015127:9,10-Dimethyl-1,2-benzanthracene; D005485:Flutamide