Differential susceptibilities of Holtzman and Sprague-Dawley rats to fetal death and placental dysfunction induced by 2, 3,7,8-teterachlorodibenzo-p-dioxin (TCDD) despite the identical primary structure of the aryl hydrocarbon receptor
Differential susceptibilities of Holtzman and Sprague-Dawley rats to fetal death and placental dysfunction induced by 2, 3,7,8-teterachlorodibenzo-p-dioxin (TCDD) despite the identical primary structure of the aryl hydrocarbon receptor
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DOI：
10.1016/j.taap.2005.08.007
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发表时间：
2006-05-01
影响因子：
3.8
通讯作者：
Ohsako, Seiichiroh
中科院分区：
文献类型：
--
作者：
Kawakami, Takashige;Ishimura, Ryuta;Ohsako, Seiichiroh
在妊娠第15天（GD15）给妊娠的Holtzman （HLZ）大鼠单次口服2,3,7,8-四氯二苯并-对二俄英（TCDD）可引起胎盘功能障碍，导致胎儿死亡（Ishimura， R., Ohsako， S., Miyabara， Y., Sakaue， M., Kawakami， T., Aoki， Y., Yonemoto， J., Tohyama， C., 2002）。2,3,7,8-四氯二苯并-对二恶英暴露后Holtzman大鼠胎盘糖原含量和葡萄糖转运蛋白3mrna水平升高Toxicol。达成。中华医学杂志（英文版）；石村，R.，大坂，S.，川上，T.，坂上，M.，青木，Y.，富山，C., 2002b。2,3,7,8-四氯二苯并-对二恶英暴露大鼠胎盘中蛋白质谱的改变和可能的缺氧Toxicol。达成。药学杂志，185,197 -206)。为了探讨tcdd诱导胎儿死亡的机制，我们比较了两种大鼠的近交品系，即HLZ大鼠和具有与HLZ大鼠相似特征的Sprague-Dawley国际遗传标准大鼠（SD-IGS）。妊娠的HLZ和SD-IGS大鼠按GD15单次灌胃给予TCDD，如括号所示（HLZ, 0、1.6 μ g TCDD/kg; SD-IGS, 0、2、5、10 μ g TCDD/kg）。尽管在高剂量的TCDD中，HLZ大鼠的GD20胎儿死亡发生率很高（14%），但在SD-IGS大鼠中，即使在最高剂量的TCDD下，也没有发生胎儿死亡。在最低剂量TCDD （1.6 μ g TCDD/kg）下，HLZ大鼠胎盘连接区出现细胞异常的组织学标志，即糖原细胞和充满嗜酸性物质的囊肿（GC-EM）的消失延迟，而SD-IGS大鼠即使在最高剂量TCDD下也没有出现这种现象。此外，暴露于TCDD的HLZ大鼠迷宫区的母血窦收缩，而SDIGS大鼠则没有。这些结果表明，与SD-IGS大鼠相比，HLZ大鼠更容易受到TCDD对胎儿生长和胎盘功能的不良影响。对芳烃受体（AhR）基因的直接测序分析显示，HLZ大鼠和SD-IGS大鼠的受体初级结构没有差异。此外，连续增加TCDD剂量（0.0125、0.05、0.2、0.8和1.6 μ g TCDD/kg）后，两株大鼠胎盘细胞色素P450 1A1、1B1、AhR和AhRR mrna的诱导水平无显著差异，表明HLZ和SD-IGS大鼠胎盘中TCDD-AhR复合物的活性相似。综上所述，上述研究结果表明，HLZ大鼠对tcdd诱导的胎盘功能障碍和胎儿死亡的易感性高于AhR，可能受HLZ大鼠遗传背景中的其他因素调节。(c) 2005爱思唯尔公司版权所有。
A single oral dose of 2,3,7,8-tetraclilorodibenzo-p-dioin (TCDD) administered to pregnant Holtzman (HLZ) rats on gestational days 15 (GD15) caused placental dysfunction, resulting in fetal death (Ishimura, R., Ohsako, S., Miyabara, Y., Sakaue, M., Kawakami, T., Aoki, Y., Yonemoto, J., Tohyama, C., 2002a. Increased glycogen content and glucose transporter 3 mRNA level in the placenta of Holtzman rats after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 178, 161-171; Ishimura, R., Ohsako, S., Kawakami, T., Sakaue, M., Aoki, Y., Tohyama, C., 2002b. Altered protein profile and possible hypoxia in the placenta of 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed rats. Toxicol. Appl. Pharmacol. 185, 197-206). In order to investigate the mechanism underlying the TCDD-induced fetal death, we compared two outbred strains of rats, namely, the HLZ and the Sprague-Dawley International Genetic Standard rats (SD-IGS), a strain with characteristics resembling those of the HLZ rats. Pregnant HLZ and SD-IGS rats were administered TCDD as a single dose by gavage on GD15, as described within the parentheses (HLZ, 0, 1.6 mu g TCDD/kg; SD-IGS, 0, 2, 5, 10 mu g TCDD/kg). Whereas a high incidence (14%) of fetal death was observed on GD20 in the HLZ rats, no fetal deaths occurred in the SD-IGS rats, even at the highest dose of TCDD. A histological marker of cellular abnormality at the placental junctional zone, i.e., delay in the disappearance of the glycogen cells and cysts filled with an eosinophilic material (GC-EM), which normally disappear by GD20, was observed in the HLZ rats after exposure to the lowest dose of TCDD (1.6 mu g TCDD/kg), but not in the SD-IGS rats even after exposure to the highest dose of TCDD. Furthermore, maternal blood sinusoids in the labyrinth zone were constricted following exposure to TCDD in the HLZ, but not SDIGS rats. These observations indicate that HLZ rats are more susceptible to the adverse effects of TCDD on fetal growth and placental function, than SD-IGS rats. Direct sequencing analysis of the aryl hydrocarbon receptor (AhR) gene revealed no difference in the primary structure of the receptor between the HLZ and SD-IGS rats. In addition, no significant differences were observed between the two strains of rats in the levels of induction of placental cytochrome P450 1A1, 1B1, AhR, and AhRR mRNAs following administration of serially increasing doses of TCDD (0.0125, 0.05, 0.2, 0.8, and 1.6 mu g TCDD/kg), indicating that the activity of TCDD-AhR complex in the placenta is similar between the HLZ and SD-IGS rats. Taken together, the above-described findings indicate that the higher susceptibility of HLZ rats to TCDD-induced placental dysfunction and fetal death may be modulated by other factor(s) in the genetic background of HLZ rats than the AhR. (c) 2005 Elsevier Inc. All rights reserved.