Acute Adverse Effects of the Indenopyridine CDB-4022 on the Ultrastructure of Sertoli Cells, Spermatocytes, and Spermatids in Rat Testes: Comparison to the Known Sertoli Cell Toxicant Di-n-pentylphthalate (DPP)

ABSTRACT: Acute effects of CDB-4022 on testicular ultrastruc-ture were determined. Rats were treated orally with vehicle ora maximally effective single dose of CDB-4022 or Di-n-pentylphtha-late (DPP). Preserved testes were processed for transmissionelectron microscopy. Sertoli and germ cells of vehicle-treated ratsdemonstrated normal morphological characteristics. Disruption ofSertoli cell ultrastructure was apparent in CDB-4022-treated rats by 3hours. A decrease in the presence of nucleoli, an increase in theamount and diameter of swollen smooth endoplasmic reticulum, anddecreases in cytoplasmic ground substance were observed. Theseverity of these degenerative effects increased at 6 and 12 hours:Vacuoles were apparent; increased cellular debris, swollen mitochon-dria, and phagocytic structures were observed; and membranes be-came more disorganized. Similar ultrastructural changes wereobserved in the Sertoli cells of DPP-treated rats. By 3 hours,spermatocytes and spermatids were adversely affected by CDB-4022 treatment with swelling of the nuclear envelope. The Step 8spermatids were especially noteworthy; chromatin was morediffuse and rarefied, the nuclear envelopes were incomplete orbroken, and the position of the spermatid nucleus within the celland relative to Sertoli cell cytoplasm was unusual. Fusion ofspermatids to form giant cells was observed by 12 hours. CDB-4022 acts acutely on Sertoli cells to induce marked cellularrarefaction and degeneration, but not necrosis. A rapid and directeffect of CDB-4022 on spermatocytes and spermatids wasobserved. The antispermatogenic activity of CDB-4022 appearsto be a consequence of direct effects on Sertoli and germ cells.Key words: Antifertility, morphology, ultrastructure, seminiferousepithelium, germ cells.J Androl 2007;28:621–629