Evaluation of the persistence of hydronephrosis induced in mice following in utero and/or lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

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.

Hydronephrosis in mice exposed to TCDD-contaminated breast milk: identification of the peak period of sensitivity and assessment of potential recovery.

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.