Couture-Haws L, Harris M W, McDonald M M, Lockhart A C, Birnbaum L S
Experimental Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Toxicol Appl Pharmacol. 1991 Mar 1;107(3):413-28. doi: 10.1016/0041-008x(91)90305-x.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of hydronephrosis in both fetal and neonatal mice. A critical period of sensitivity to TCDD could not be identified for prenatally induced hydronephrosis since the urinary tract appeared equally sensitive throughout organogenesis. To identify the critical period of susceptibility for development of lactationally induced hydronephrosis in neonatal mice, as well as to characterize the potential for recovery from this renal lesion, dose-response and time-course studies were conducted in the postnatal period. Pregnant C57BL/6N mice were allowed natural delivery. In the dose-response phase of this investigation, mothers were administered 0, 3, 6, or 12 micrograms TCDD/kg once by gavage on Postnatal Day (PND) 1, 4, 8, or 14, and dams and pups were euthanized on PND 26. The kidneys were examined, and hydronephrotic severity was scored. The incidence and severity of hydronephrosis were significantly increased above controls only following treatment on PND 1 or 4, while on PND 8 the increase was marginal and pairwise tests were nonsignificant. Following treatment of dams on PND 1, the hydronephrotic response detected in 26-day-old pups was significantly greater than that for all later exposure days. In the time-course study, dams were given a single oral dose of 0 or 9 micrograms TCDD/kg on PND 1, and mothers and litters were subsequently euthanized on PND 7, 13, 19, or 26. Both hydronephrotic incidence and severity increased with time to euthanization following treatment on PND 1. Thus with the dosing regimen used in this study, recovery does not appear to occur between PNDs 7 and 26. Sex-related differences were observed, as the hydronephrotic response in males was generally greater than in females. In conclusion, the postnatal window of sensitivity during which TCDD can induce hydronephrosis is very narrow. Nonetheless, the hydronephrotic response induced during this early postnatal time is dramatic. Finally, PND 1 is the peak postnatal period of susceptibility for development of TCDD-induced hydronephrosis.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种在胎儿和新生小鼠中均能有效诱发肾积水的物质。由于在整个器官发生过程中尿路似乎都同样敏感，因此无法确定产前诱发肾积水对TCDD敏感的关键时期。为了确定新生小鼠哺乳期诱发肾积水发展的易感关键时期，并描述从这种肾脏病变中恢复的可能性，在出生后进行了剂量反应和时间进程研究。让怀孕的C57BL/6N小鼠自然分娩。在本研究的剂量反应阶段，在出生后第（PND）1、4、8或14天，通过灌胃给母鼠一次性给予0、3、6或12微克TCDD/千克，在PND 26时对母鼠和幼崽实施安乐死。检查肾脏，并对肾积水严重程度进行评分。仅在PND 1或4进行处理后，肾积水的发生率和严重程度才显著高于对照组，而在PND 8时增加幅度较小且两两比较无显著差异。在PND 1对母鼠进行处理后，在26日龄幼崽中检测到的肾积水反应明显大于所有后续暴露日的反应。在时间进程研究中，在PND 1给母鼠单次口服0或9微克TCDD/千克，随后在PND 7、13、19或26时对母鼠及其幼崽实施安乐死。在PND 1进行处理后，肾积水的发生率和严重程度均随着安乐死时间的推移而增加。因此，采用本研究中的给药方案，在PND 7至26之间似乎不会发生恢复。观察到了性别相关差异，因为雄性的肾积水反应通常大于雌性。总之，TCDD能够诱发肾积水的出生后敏感窗口期非常狭窄。尽管如此，在出生后早期诱发的肾积水反应却很显著。最后，PND 1是TCDD诱发肾积水发展的出生后易感高峰期。
