Differential effects of octylphenol, 17beta-estradiol, endosulfan, or bisphenol A on the steroidogenic competence of cultured adult rat Leydig cells.
In the current studies, we evaluated the effects of 4-tert-octylphenol (OP), endosulfan, bisphenol A (BPA), and 17beta-estradiol on basal or hCG-stimulated testosterone formation by cultured Leydig cells from young adult male rats. Exposure of Leydig cells to increasing concentrations of OP (1 to 2000 nM), 17beta-estradiol (1 to 1000 nM), endosulfan (1 to 1000 nM) or BPA (1 to 1000 nM), alone or with 10 mIU/mL hCG for 4 or 24 h, did not lower ambient testosterone levels, although cells exposed to higher OP concentrations + hCG for 24 h often had modest declines in testosterone (10 to 20%). Of interest, exposure to the highest concentration OP (2000 nM) alone for 4 or 24 h increased testosterone levels (approximately 2-fold in 4-h exposed cells). Whether prior exposure to OP + hCG for 24 h affects the subsequent conversion of steroid substrates to testosterone over 4 h was evaluated. Progressive declines in 1 microM 22(R) hydroxycholesterol, 1 microM pregnenolone, or 1 microM progesterone conversion to testosterone was observed beginning at 100 to 500 nM OP exposure (maximal declines of 40 to 12% of controls were observed); however, the conversion of 1 microM androstenedione to testosterone was not affected by OP. These results suggested that 24-h exposure to OP + hCG has no effect on 17beta-hydroxysteroid dehydrogenase, which converts androstenedione to testosterone, but that it inhibits the 17alpha-hydroxylase/C17-20 lyase step, which converts progesterone to androstenedione. In addition, potentially, OP could inhibit cholesterol side/chain cleavage activity, which converts cholesterol to pregnenolone, and/or 3beta-hydroxysteroid dehydrogenase, which converts pregnenolone to progesterone. Of interest, exposure to increasing concentrations of 17beta-estradiol (1 to 1000 nM), endosulfan (1 to 1000 nM), or BPA (1 to 1000 nM) + hCG for 24 h had no effect on subsequent conversion of 22(R)hydroxycholesterol to testosterone. Furthermore, the inhibiting effects of OP + hCG exposure on subsequent conversion of progesterone to testosterone was unaffected by concomitant exposure to the pure estrogen antagonist, ICI 182,780, or the antioxidants, ascorbate or dimethyl sulfoxide, suggesting that the actions of OP are not mediated through binding to estrogen receptor alpha or beta or by free radical induced damage to steroidogenic enzymes, respectively. These results demonstrate that direct exposure of adult Leydig cells to OP may have subtle effects on their ability to produce testosterone, which may not be detected by measuring ambient androgen levels. In addition, the effects of OP on Leydig cell testosterone formation appear to be different from those of the native estrogen, 17beta-estradiol, and from other reported weak xenoestrogens such as endosulfan and BPA.
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Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Health Effect Laboratory Division, Morgantown, WV 26505-2888, USA. eem8@cdc.gov
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de León
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D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004726:Endosulfan / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006888:Hydroxycholesterols / Q000378:metabolism; D007985:Leydig Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010636:Phenols / Q000494:pharmacology*; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000096:biosynthesis*; D000098826:Bisphenol A Compounds
D000735:Androstenedione; D001559:Benzhydryl Compounds; D006063:Chorionic Gonadotropin; D004726:Endosulfan; D004958:Estradiol; D004965:Estrogen Antagonists; D006888:Hydroxycholesterols; D010636:Phenols; D011284:Pregnenolone; D011374:Progesterone; D013739:Testosterone; C105260:4-tert-octylphenol; C006780:bisphenol A; D000098826:Bisphenol A Compounds