Fetal testosterone insufficiency and abnormal proliferation of Leydig cells and gonocytes in rats exposed to di(n-butyl) phthalate.
Adult male rats previously exposed on gestation days (GD) 12-21 to di(n-butyl) phthalate (DBP) have reproductive tract malformations, particularly agenesis of the epididymis, decreased sperm production, and Leydig cell hyperplasia and adenomas. Although similar effects are produced by the potent androgen receptor (AR) antagonist flutamide and are indicative of disruption of male sexual differentiation via an antiandrogenic mechanism, DBP is not an AR antagonist. The purpose of the study was to determine whether DBP causes pathologic changes and alterations in androgen status in the testis during the prenatal period of male reproductive tract differentiation. Pregnant CD rats were given corn oil, DBP (500 mg/kg/day), or flutamide (100 mg/kg/day) p.o. on GD 12-21. At GD 16-21, DBP caused hyperplasia of Leydig cells, many of which were 3beta-hydroxysteroid dehydrogenase- and/or AR-positive. Focal areas of hyperplasia had increased numbers of Leydig cells positive for proliferating cell nuclear antigen (PCNA). At GD 21, testis atrophy was apparent, seminiferous cords in DBP-exposed fetuses were enlarged and contained multinucleated gonocytes that, unlike controls, were PCNA-positive. DBP, but not flutamide, markedly decreased testicular testosterone levels at GD 18 and 21. Fewer epididymal ducts and reduced AR staining in some ducts were evident with DBP treatment, whereas decreased overall AR staining was seen with flutamide in the presence of mild Leydig cell hyperplasia. Leydig cell proliferation is likely a compensatory mechanism to increase testicular steroidogenesis triggered by testosterone insufficiency. The overall decrease in androgen concentration is not corrected and results in reproductive tract malformations. The multinuclearity and proliferation of gonocytes suggests an underlying Sertoli cell dysfunction.
Mylchreest
Eve
E
CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA.
Sar
Madhabananda
M
Wallace
Duncan G
DG
Foster
Paul M D
PM
D000014:Abnormalities, Drug-Induced / Q000378:metabolism / Q000473:pathology; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003993:Dibutyl Phthalate / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D005485:Flutamide / Q000633:toxicity; D006965:Hyperplasia / Q000139:chemically induced; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012733:Sex Differentiation / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000096:biosynthesis*
D000726:Androgen Antagonists; D018809:Proliferating Cell Nuclear Antigen; D003993:Dibutyl Phthalate; D013739:Testosterone; D005485:Flutamide