Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: Effects of low versus high doses
Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: Effects of low versus high doses
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DOI：
10.1006/taap.2002.9459
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发表时间：
2002-08-15
影响因子：
3.8
通讯作者：
vom Saal, FS
中科院分区：
文献类型：
--
作者：
Alworth, LC;Howdeshell, KL;vom Saal, FS
我们研究了胎儿暴露于低剂量药物己烯雌酚（DES）（0.1杯/千克/天）和杀虫剂甲氧氯（MXC）（10杯/千克/天）以及1000倍高剂量（100杯/千克/天DES和10,000杯/千克/天MXC）对雌性CD-1小鼠的影响。怀孕的雌性在怀孕12-18天给予这些化学物质。在7-8月龄时，切除雌性后代卵巢，植入含有雌二醇的硅胶胶囊7天。与对照组相比，暴露于0.1杯DES剂量的女性子宫明显变重，而暴露于100杯DES剂量的女性子宫明显变轻。产前暴露于10马克杯/公斤剂量MXC的雌性子宫明显比暴露于10,000马克杯/公斤剂量MXC的雌性子宫重，但两组与对照组均无显著差异。暴露于两种剂量DES的女性肝脏重量明显大于对照组。使用微阵列方法分析DNA甲基化，观察到核糖体DNA （rDNA）甲基化的增加。序列数据和Southern分析表明，在产前暴露于低剂量和高剂量DES的子宫样本中，18S rDNA和45S pre-rDNA甲基化增加。因此，我们发现胎儿暴露于低剂量和高剂量DES对子宫对雌二醇的反应有相反的影响（倒u型剂量-反应关系）。相反，产前DES暴露对肝脏重量和核糖体DNA高甲基化均存在单调的剂量-反应关系。(C) 2002 Elsevier Science （USA）。
We examined the effects on female CD-1 mice of fetal exposure to low doses of the drug diethylstilbestrol (DES) (0.1 mug/kg/day) and the insecticide methoxychlor (MXC) (10 mug/kg/day) as well as 1000-fold higher doses: 100 mug/kg/day DES and 10,000 mug/kg/day MXC. Pregnant females were administered these chemicals on gestation days 12-18. At 7-8 months of age, female offspring were ovariectomized and implanted for 7 days with a Silastic capsule containing estradiol. Relative to controls, females exposed to the 0.1 mug DES dose showed significantly heavier uteri, while females exposed to the 100 mug DES dose showed significantly lighter uteri. Females exposed prenatally to the 10 mug/kg dose of MXC had significantly heavier uteri relative to females exposed to the 10,000 mug/kg dose of MXC, but neither group differed significantly from controls. Liver weight for females exposed to both doses of DES was significantly greater than controls. Using a microarray approach to analyze DNA methylation, an increase in ribosomal DNA (rDNA) methylation was observed. Sequence data and Southern analysis indicate an increase in 18S rDNA and 45S pre-rDNA methylation in uterine samples exposed prenatally to low and high doses of DES. We thus found opposite effects of fetal exposure to a low and a high dose of DES on the uterine response to estradiol (inverted-U dose-response relationship). In contrast, there was a monotonic dose-response relationship found for prenatal DES exposure on both liver weight and ribosomal DNA hypermethylation. (C) 2002 Elsevier Science (USA).