You L, Chan S K, Bruce J M, Archibeque-Engle S, Casanova M, Corton J C, Heck H
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina, 27709-2137, USA.
Toxicol Appl Pharmacol. 1999 Jul 15;158(2):197-205. doi: 10.1006/taap.1999.8694.
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) causes sexual developmental aberrations in male rats through a likely mechanism of androgen receptor antagonism. DDE is also known to induce liver cytochrome P-450 (CYP). The expression of CYP enzymes is regulated by steroid hormones, which, in turn, are inactivated in the liver by CYP-catalyzed hydroxylations and subsequent conjugations. This study was undertaken to examine the potential of in utero DDE exposure to affect the developmental expression of the hepatic CYP enzymes that are responsible for testosterone hydroxylations. Pregnant Sprague-Dawley rats were dosed daily by gavage with DDE at 0, 10, or 100 mg/kg body weight or with flutamide at 40 mg/kg body weight from gestation day 14 to 18. Additional adult male rats were given seven daily doses of DDE at 100 mg/kg. Liver samples were collected from the offspring of the dosed dams on postnatal days (PND) 10 and 21 and from the adult rats a day after the last dosing. Assays for regioselective and sterospecific testosterone hydroxylase activities were performed using hepatic microsomal preparations. Specific liver CYP proteins were detected by immunoblotting. While the CYP2B1 and 3A1 and their hydroxylated testosterone products were highly elevated by the DDE treatments in both adult and developing rats, the responses of 2C11 and 2A1 were development-dependent. The flutamide treatment had little effect on CYP enzyme expression. This study demonstrated that developing offspring rats are susceptible to the hepatic CYP enzyme-modulating action of DDE following its administration to the pregnant dams.
1,1-二氯-2,2-双（对氯苯基）乙烯（DDE）通过可能的雄激素受体拮抗作用机制导致雄性大鼠性发育异常。已知DDE还可诱导肝脏细胞色素P-450（CYP）。CYP酶的表达受类固醇激素调节，而类固醇激素又在肝脏中通过CYP催化的羟基化及随后的结合反应而失活。本研究旨在探讨子宫内暴露于DDE对负责睾酮羟基化的肝脏CYP酶发育表达的潜在影响。从妊娠第14天至18天，对怀孕的Sprague-Dawley大鼠每日经口灌胃给予0、10或100 mg/kg体重的DDE或40 mg/kg体重的氟他胺。另外，对成年雄性大鼠每日给予7次剂量为100 mg/kg的DDE。在出生后第10天和21天从给药母鼠的后代收集肝脏样本，并在最后一次给药后一天从成年大鼠收集肝脏样本。使用肝微粒体制剂进行区域选择性和立体特异性睾酮羟化酶活性测定。通过免疫印迹检测特定的肝脏CYP蛋白。虽然在成年和发育中的大鼠中，DDE处理均使CYP2B1和3A1及其羟基化睾酮产物高度升高，但2C11和2A1的反应具有发育依赖性。氟他胺处理对CYP酶表达影响很小。本研究表明，在给怀孕母鼠施用DDE后，发育中的后代大鼠易受其肝脏CYP酶调节作用的影响。
