4- Tert-octylphenol (octylphenol, OP) is a degradation product of a1kylphenol ethoxylates, widely used as a surfactant additive in the manufacture of detergents, plastics and pesticides. OP has been reported to mimic estrogen in many cellular systems and, thus, to potentially alter normal sexual growth/maturation. In the present studies, the direct effects of OP on 10 mIU/ml human chorionic gonadotropin (hCG)- stimulated testosterone (T) biosynthesis by cultured PC and ILC were examined. PC are mesenchymal cells that differentiate into ILC, mainly through the actions of luteinizing hormone, between approximately 14 to 28 d after birth, and ILC are converted to adult Leydig cells during the next 4 to 5 weeks of maturation. PC and ILC were isolated by elutriation and Percoll gradient centrifugation of collagenase-dispersed testes from 23-day-old Sprague-Dawley rats. Increasing concentrations of OP (1-2000 nM) progressively decreased hCG-stimulated T starting at 100 or 500 nM, to maximal declines of 30 to 70% below control at the highest concentration in both PC and ILC following exposure for 24 h. OP, similarly, decreased 1 mM 8-Br-cAMP-stimulated T in both PC and ILC, suggesting that the main site(s) of action occur after cAMP formation. To further localize the site(s) of action of OP, the conversion of uM 22 (R) hydroxycholesterol, pregnenolone, progesterone or androstenedione to T after exposure to increasing OP concentrations and hCG was evaluated. Progressive declines in 22 (R) hydroxycholesterol, pregnenolone and progesterone conversion to T were observed, but not androstenedione, suggesting that P450c17 activity, which converts progesterone to androstenedione, is inhibited by OP but not 17 beta hydroxysteroid dehydrogenase activity, which converts androstenedione to T. OP also may inhibit cholesterol side-chain cleavage and 3 beta-hydroxysteroid dehydrogenase-isomerase activities, but additional studies are necessary to confirm this possibility. Interestingly, 17 beta-estradiol (1-1000 nM) had no effect on hCG-stimulated T formation in both PC and ILC, and concomitant exposure to 100 nM ICI 182,780, a pure estrogen antagonist, did not alter the inhibitive effects of OP. These results suggest that OP effects on both PC and ILC do not mimic the actions of estrogen and are not mediated through the classic estrogen receptor - approximately or beta pathway.
The Toxicologist. Society of Toxicology 39th Annual Meeting, March 19-23, 2000, Philadelphia, Pennsylvania