Murono Eisuke P, Derk Raymond C
Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Pathology and Physiology Research Branch, M/S L-2015, 1095 Willowdale Road, Morgantown, WV 26505-2888, USA.
Reprod Toxicol. 2005 Nov-Dec;20(4):503-13. doi: 10.1016/j.reprotox.2005.03.002.
Methoxychlor (MC) is an insecticide that is presently used on agricultural crops, especially after the ban on the use of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) in the United States. Following administration in vivo, MC is converted to 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which is thought to be the active agent. However, both MC and HPTE have been reported to have weak estrogenic and antiandrogenic activities, and they are thought to exert their potential adverse (endocrine disruptive) effects through the estrogen and androgen receptors, respectively. In a recent study, HPTE was shown to inhibit both basal and hCG-stimulated testosterone production by cultured Leydig cells from immature and adult rats, and these effects were reported to be mediated through the estrogen receptor. Because fetal Leydig cells represent a separate population from adult Leydig cells and many of the reported adverse actions of endocrine disruptors are thought to have their effects during gestational exposure, the present studies examined the effects of HPTE on testosterone formation by cultured fetal Leydig cells from neonatal rats to determine whether these cells are sensitive to HPTE. Our studies demonstrated that HPTE inhibited both basal and hCG-stimulated testosterone formation in a dose-dependent manner. Significant declines in testosterone were observed at about 100nM HPTE, and this effect was detected as early as 1h after exposure. The main effects of HPTE appeared to be localized to the cholesterol side-chain cleavage step which converts cholesterol to pregnenolone. In addition, this effect did not appear to be mediated through the estrogen receptor as a weak estrogen or the androgen receptor as an antiandrogen, which are the currently proposed modes of action of MC and HPTE.
甲氧滴滴涕（MC）是一种目前用于农作物的杀虫剂，尤其是在美国禁止使用2,2-双（对氯苯基）-1,1,1-三氯乙烷（滴滴涕）之后。在体内给药后，MC会转化为2,2-双（对羟基苯基）-1,1,1-三氯乙烷（HPTE），后者被认为是活性剂。然而，据报道MC和HPTE都具有微弱的雌激素活性和抗雄激素活性，并且它们被认为分别通过雌激素和雄激素受体发挥其潜在的不良（内分泌干扰）作用。在最近的一项研究中，HPTE被证明可抑制来自未成熟和成年大鼠的培养睾丸间质细胞的基础睾酮分泌以及人绒毛膜促性腺激素（hCG）刺激的睾酮分泌，并且据报道这些作用是通过雌激素受体介导的。由于胎儿睾丸间质细胞与成年睾丸间质细胞是不同的细胞群体，并且许多已报道的内分泌干扰物的不良作用被认为在孕期暴露时会产生影响，因此本研究检测了HPTE对新生大鼠培养的胎儿睾丸间质细胞睾酮生成的影响，以确定这些细胞是否对HPTE敏感。我们的研究表明，HPTE以剂量依赖的方式抑制基础睾酮分泌以及hCG刺激的睾酮分泌。在约100nM的HPTE浓度下观察到睾酮显著下降，并且在暴露后1小时就检测到了这种作用。HPTE的主要作用似乎定位于将胆固醇转化为孕烯醇酮的胆固醇侧链裂解步骤。此外，这种作用似乎不是通过作为弱雌激素的雌激素受体或作为抗雄激素的雄激素受体介导的，而这是目前所提出的MC和HPTE的作用模式。
