Sheehan D M, Branham W S, Medlock K L, Shanmugasundaram E R
Teratology. 1984 Jun;29(3):383-92. doi: 10.1002/tera.1420290309.
Fusarium sp. contaminated feedstuffs elicit adverse estrogenic effects in several commercially important animal species via the mycotoxin zearalenone. An estrogenically active synthetic derivative, zearalanol, is used as an anabolic agent in cattle. Since estrogens can irreversibly alter target tissue development, we investigated the estrogenic activity of these compounds in the neonatal rat uterus. Both induced dose-dependent premature uterine growth when injected daily on postnatal days 1-5 (ED50 = 1.3 mg/kg BW). Nuclear estrogen receptor levels dramatically increased 1 hour after either a single injection on day 5 or after five daily injections. In 5-day-old animals, the translocated nuclear receptor was characterized as a single class of binding sites with a dissociation constant (KD) for estradiol (E2) of 1 nM. At 15 days, zearalanol-treated animals showed greater uterine nuclear receptor retention than zearalenone-treated animals. In 5-day-old animals, single mycotoxin doses induced five fold elevations of ornithine decarboxylase (ODC) at 6 hours. Unlike the growth response, ODC dose-response studies showed zearalanol to be about 20-fold more effective than zearalenone. Time course studies revealed that a low dose of zearalenone, but not of zearalanol, resulted in a shift in peak activity from 6 to 8 hours. These data suggest that metabolism of zearalenone may be important in short-term pharmacodynamics. In a competitive binding assay, neither compound competed [3H]E2 from the E2 binding site on alpha-fetoprotein. We conclude that the uterine growth response and ODC induction demonstrate the neonatal estrogenic action of these mycotoxins, apparently mediated via the estrogen receptor. The greater effectiveness of zearalanol in inducing ODC may be related to nuclear retention and/or zearalenone metabolism.
镰刀菌属污染的饲料通过霉菌毒素玉米赤霉烯酮在几种具有重要商业价值的动物物种中引发不良雌激素效应。一种具有雌激素活性的合成衍生物，玉米赤霉醇，被用作牛的合成代谢剂。由于雌激素可不可逆地改变靶组织发育，我们研究了这些化合物在新生大鼠子宫中的雌激素活性。在出生后第1 - 5天每日注射时，二者均诱导剂量依赖性的子宫过早生长（半数有效剂量 = 1.3 mg/kg体重）。在第5天单次注射或每日注射5次后1小时，核雌激素受体水平显著增加。在5日龄动物中，转位的核受体被表征为一类单一的结合位点，对雌二醇（E2）的解离常数（KD）为1 nM。在15日龄时，玉米赤霉醇处理的动物比玉米赤霉烯酮处理的动物表现出更高的子宫核受体保留率。在5日龄动物中，单次霉菌毒素剂量在6小时时诱导鸟氨酸脱羧酶（ODC）升高五倍。与生长反应不同，ODC剂量反应研究表明玉米赤霉醇的效力比玉米赤霉烯酮高约20倍。时间进程研究表明，低剂量的玉米赤霉烯酮而非玉米赤霉醇导致峰值活性从6小时转移至8小时。这些数据表明玉米赤霉烯酮的代谢在短期药效学中可能很重要。在竞争性结合试验中，两种化合物均未从甲胎蛋白上的E2结合位点竞争[3H]E2。我们得出结论，子宫生长反应和ODC诱导证明了这些霉菌毒素的新生雌激素作用，显然是通过雌激素受体介导的。玉米赤霉醇在诱导ODC方面更高的效力可能与核保留和/或玉米赤霉烯酮代谢有关。
