Couture-Haws L, Harris M W, 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):402-12. doi: 10.1016/0041-008x(91)90304-w.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an extremely potent teratogen in mice, inducing structural malformations in the kidney and secondary palate. Maternal depots of TCDD, stored primarily in adipose tissue, are mobilized during the nursing period. Thus, lactation serves as a significant route of exposure for the developing neonate. The objective of this present investigation was to assess whether hydronephrosis persisted postnatally, as well as to determine if the renal lesion could be induced lactationally. Pregnant C57BL/6N mice were treated once by gavage with 0, 3, or 12 micrograms TCDD/kg body wt on Gestation Day (GD) 6. All dams were allowed to litter, and each litter was standardized at random to a size of six pups. Standardized litters were then reciprocally cross-fostered on the day of birth. Postnatal Day (PND) 0, resulting in the establishment of four experimental groups: pups not exposed by either route, pups exposed only in utero, pups exposed only lactationally, and pups exposed by both routes. Pups were euthanized at one of two time points, either at weaning (PND 25) or at puberty (PND 67). TCDD was not overtly toxic to the dams or neonates with the dosing regime used in this study. Hydronephrotic incidence and severity, while greatest for pups receiving dual exposure, were essentially the same for pups exposed in utero only vs lactationally only. Lactational exposure induced hydronephrosis (HN), as well as exacerbated the severity of existing HN which was induced in utero. Regardless of the exposure group, the severity of the renal lesion was always greater in the right kidney than in the left. There were no sex-related differences in either the incidence or the severity of HN, nor was there any difference in response between PNDs 25 and 67. These data suggest that the renal lesion persists from weaning through puberty, despite the cessation of exposure. However, the data indicate that partial recovery from HN induced in utero occurs during the early postnatal period, as both hydronephrotic incidence and severity decreased with increasing age between GD 18 and PND 25. Recovery was most pronounced in the left kidney regardless of dose, thus suggesting that the ability to recover may in part be dependent upon the extent of renal damage.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种对小鼠极具致畸性的物质，可导致肾脏和继发腭出现结构畸形。TCDD在母体中的储存库主要存在于脂肪组织中，在哺乳期会被调动起来。因此，哺乳是发育中的新生儿的一个重要暴露途径。本研究的目的是评估肾盂积水在出生后是否持续存在，以及确定肾脏病变是否可通过哺乳诱导产生。在妊娠第6天（GD6），对怀孕的C57BL/6N小鼠通过灌胃一次性给予0、3或12微克TCDD/千克体重。所有母鼠均正常产仔，每窝随机标准化为6只幼崽。标准化后的幼崽在出生当天进行相互交叉寄养。出生后第0天（PND0），由此建立了四个实验组：未通过任何一种途径暴露的幼崽、仅在子宫内暴露的幼崽、仅在哺乳期暴露的幼崽以及通过两种途径暴露的幼崽。幼崽在两个时间点之一被安乐死，即在断奶时（PND25）或青春期时（PND67）。本研究中使用的给药方案对母鼠或新生儿没有明显毒性。肾盂积水的发生率和严重程度，虽然对于接受双重暴露的幼崽最高，但仅在子宫内暴露的幼崽与仅在哺乳期暴露的幼崽基本相同。哺乳期暴露会诱发肾盂积水（HN），并加重子宫内诱发的现有HN的严重程度。无论暴露组如何，右肾的肾脏病变严重程度总是高于左肾。HN的发生率或严重程度均无性别差异，在PND25和PND67之间的反应也没有差异。这些数据表明，尽管暴露停止，但肾脏病变从断奶持续到青春期。然而，数据表明，子宫内诱发的HN在出生后早期会出现部分恢复，因为在GD18至PND25之间，肾盂积水的发生率和严重程度均随着年龄增长而降低。无论剂量如何，左肾的恢复最为明显，因此表明恢复能力可能部分取决于肾脏损伤的程度。
