Buchanan David L, Ohsako Seiichiro, Tohyama Chiharu, Cooke Paul S, Iguchi Taisen
Center for Integrative Bioscience, Okazaki National Research Institutes, Okazaki, Aichi 444-8585, Japan.
Toxicol Sci. 2002 Mar;66(1):62-8. doi: 10.1093/toxsci/66.1.62.
A single dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD; 5 microg/kg, ip) inhibits 17beta-estradiol (E2)-induced uterine epithelial mitogenesis, apparently through disruption of stromal-epithelial interactions. To understand if TCDD alters early uterine (Ut) responses to E2, young adult C57BL/6J mice were ovariectomized and given (i.p.) either oil or 5 microg/kg TCDD. After 24 h, TCDD-treated mice received E2, and oil-treated mice were given E2 or oil. Body and Ut weights were collected 6 and 18 h later. Ut were flash-frozen at 6 h. E2 increased Ut weight (p < 0.0001) and Ut/body weight ratio (p < 0.0001), compared to mice given oil alone. Ut cyclin expression was assessed by an RNase protection assay. E2 increased mRNA expression for cyclin A2 and B1 (p < 0.05), in addition to D1, D2, and D3 (p < 0.001), while cyclin C was unchanged from oil controls and cyclins A1 and B2 were undetectable. In contrast, TCDD completely abolished E2-induced cyclin A2, which has been associated with S phase initiation, and reduced B1 and D2 (p < 0.05). Interestingly, TCDD did not alter E2-induced Ut weight increases at 6 h, but inhibited E2-induced Ut weight gain at 18 h. A 10-microg/kg TCDD dose was necessary for attenuation of the early E2-induced Ut weight increases (p < 0.01). Since TGF-beta regulates cyclins, Ut TGF-beta was also assessed in TCDD + E2-treated and control mice. TGF-beta mRNA levels were increased after TCDD compared to E2 alone (p < 0.01), suggesting a possible mechanism for TCDD inhibition of Ut cyclin A2. Thus, TCDD alters specific E2-regulated Ut G(1) phase activities and may inhibit E2-induced Ut epithelial mitogenesis by disrupting specific cell signaling mechanisms necessary for S phase initiation in vivo.
单次剂量的二噁英（2,3,7,8-四氯二苯并对二噁英或TCDD；5微克/千克，腹腔注射）可抑制17β-雌二醇（E2）诱导的子宫上皮细胞有丝分裂，显然是通过破坏基质-上皮细胞间的相互作用来实现的。为了解TCDD是否改变子宫（Ut）对E2的早期反应，将年轻成年C57BL/6J小鼠进行卵巢切除，并腹腔注射油剂或5微克/千克TCDD。24小时后，给TCDD处理组小鼠注射E2，给油剂处理组小鼠注射E2或油剂。6小时和18小时后测量体重和子宫重量。6小时时将子宫快速冷冻。与仅注射油剂的小鼠相比，E2使子宫重量（p<0.0001）和子宫/体重比（p<0.0001）增加。通过核糖核酸酶保护试验评估子宫细胞周期蛋白的表达。E2使细胞周期蛋白A2、B1（p<0.05）以及D1、D2和D3（p<0.001）的mRNA表达增加，而细胞周期蛋白C与油剂对照组相比无变化，细胞周期蛋白A1和B2未检测到。相反，TCDD完全消除了与S期起始相关的E2诱导的细胞周期蛋白A2，并使B1和D2减少（p<0.05）。有趣的是，TCDD在6小时时未改变E2诱导的子宫重量增加，但在18小时时抑制了E2诱导的子宫重量增加。10微克/千克的TCDD剂量对于减弱早期E2诱导的子宫重量增加是必要的（p<0.01）。由于转化生长因子-β（TGF-β）调节细胞周期蛋白，因此也对TCDD + E2处理组和对照组小鼠的子宫TGF-β进行了评估。与仅使用E2相比，TCDD处理后TGF-β的mRNA水平升高（p<0.01），这提示了TCDD抑制子宫细胞周期蛋白A2的一种可能机制。因此，TCDD改变了E2特异性调节的子宫G1期活性，并可能通过破坏体内S期起始所需的特定细胞信号传导机制来抑制E2诱导的子宫上皮细胞有丝分裂。
