Suppression of fetal testicular cytochrome P450 17 by maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: a mechanism involving an initial effect on gonadotropin synthesis in the pituitary.
The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the fetal expression of testicular cytochrome P450 17 (CYP17), one of the enzymes necessary for sex steroid synthesis, was studied in Wistar rats. Fetal testicular CYP17 exhibited reduced mRNA and protein levels following exposure of the dams at gestational day 15 to 1 microg/kg TCDD. In support of this, CYP17 activity catalyzed by fetal testis homogenate was also reduced by maternal exposure to TCDD. The reduction in CYP17 expression seemed to be specific for fetal stages, because 7 day-old pups born from TCDD-treated dams did not exhibit any reduction in CYP17. In sharp contrast to the in vivo observations, TCDD failed to reduce CYP17 expression in cultured fetal testis, although CYP17 could be induced by activating cAMP-dependent signaling. To assess the role of pituitary luteinizing hormone (LH) on TCDD-induced reduction in fetal testicular CYP17, a further investigation was performed to examine whether the direct injection of LH into fetuses restores the altered CYP17 expression. The results showed that in utero injection of equine chorionic gonadotropin, an LH-mimicking hormone, completely abolishes the TCDD-produced reduction in fetal CYP17. However, neither the alpha- nor beta-subunits of LH in cultured fetal pituitary was reduced by TCDD. These results suggest that 1) maternal exposure to TCDD impairs the expression of testicular CYP17 in a fetal stage-specific manner; 2) this effect is due, at least partially, to a TCDD-produced reduction in circulating LH; and 3) TCDD exerts such an effect by affecting the upstream mechanism regulating the pituitary synthesis of LH.
Taketoh
Junko
J
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Mutoh
Junpei
J
Takeda
Tomoki
T
Ogishima
Tadashi
T
Takeda
Shuso
S
Ishii
Yuji
Y
Ishida
Takumi
T
Yamada
Hideyuki
H
D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006064:Gonadotropins, Equine / Q000494:pharmacology; D007267:Injections; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D007986:Luteinizing Hormone / Q000096:biosynthesis*; D008297:Male; D018811:Maternal Exposure; D009924:Organ Culture Techniques; D010902:Pituitary Gland / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D013737:Testis / Q000196:embryology / Q000201:enzymology*
D004785:Environmental Pollutants; D006064:Gonadotropins, Equine; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D007986:Luteinizing Hormone; D000242:Cyclic AMP; D019363:Cytochrome P-450 CYP1A1; D013254:Steroid 17-alpha-Hydroxylase