Effects of CDB-4022 on Leydig cell function in adult male rats.
CDB-4022, an indenopryridine, suppresses spermatogenesis and decreases inhibin secretion in adult male rats. In the present study, we investigated the effects of CDB-4022 on Leydig cell function. A single oral dose of CDB-4022 (2.5 mg/kg) resulted in a 2-fold decrease in serum testosterone levels after 7 days that was paralleled by a decrease in Cyp17a1 mRNA and protein levels and 17alpha hydroxylase enzymatic activity compared with vehicle-treated rats. Consistent with the lower serum testosterone levels, pituitary Lhb and Fshb mRNA levels were increased 3.2- and 2.3-fold, respectively, by CDB-4022 treatment. Ultrastructural analysis of pituitary gonadotrophs showed distended endoplasmic reticulum (ER) and fewer secretory granules in CDB-4022-treated rats, characteristic of enhanced secretory activity. Conversely, CDB-4022 increased serum progesterone levels, testicular Star mRNA and protein expression, and the number of Leydig cells per testis. Serum inhibin B levels were undetectable in CDB-4022-treated rats, while serum activin A levels were similar to controls, indicating that the CDB-4022-treated rats have an elevated activin A:inhibin B ratio. In the presence of hCG stimulation, activin A directly suppressed testosterone secretion but enhanced progesterone secretion from rat Leydig cell primary cultures. Likewise, treatment of MA-10 cells with activin A was found to enhance cAMP-stimulated progesterone secretion and STAR expression. Together, our data indicate that CDB-4022 treatment inhibits CYP17A1 and stimulates STAR expression, thereby decreasing testosterone but increasing progesterone production. We propose that unopposed actions of activin A most likely contribute to the steroid profile in rats after CDB-4022 treatment. Our findings establish CDB-4022 as a new model to examine intratesticular control mechanisms that modulate Leydig cell gene expression and function.
Chen
Yu-Chyu
YC
Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky 40202, USA.
Cochrum
Renate K
RK
Tseng
Michael T
MT
Ghooray
Dushan T
DT
Moore
Joseph P
JP
Winters
Stephen J
SJ
Clark
Barbara J
BJ
D028341:Activins / Q000097:blood / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D012739:Gonadal Steroid Hormones / Q000097:blood / Q000378:metabolism*; D007192:Indenes / Q000494:pharmacology*; D007265:Inhibins / Q000097:blood; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D010902:Pituitary Gland / Q000378:metabolism / Q000648:ultrastructure; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
C435918:CDB 4022; D012739:Gonadal Steroid Hormones; D007192:Indenes; D010750:Phosphoproteins; D010880:Piperidines; C422405:activin A; C422364:inhibin B; D000098682:Steroidogenic Acute Regulatory Protein; D028341:Activins; D007265:Inhibins; D012313:RNA; D013254:Steroid 17-alpha-Hydroxylase