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ADVERSE EFFECTS OF TCDD ON MAMMARY GLAND DEVELOPMENT IN LONG EVANS RATS: A TWO GENERATIONAL STUDY
Citation:
Fenton, S E., J. T. Hamm, L S. Birnbaum, AND G. L. Youngblood. ADVERSE EFFECTS OF TCDD ON MAMMARY GLAND DEVELOPMENT IN LONG EVANS RATS: A TWO GENERATIONAL STUDY. Presented at Dioxin 2000 Meeting, Monteray, CA, August 14-18, 2000.
Description:
Recent studies have demonstrated variable effects on mammary gland development in rat offspring exposed to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, 1 ug/kg, gavage) on day 15 of gestation. We have characterized these effects in Long Evans rats, in both one and two-generational studies using carmine-stained whole mount comparisons. The mammary epithelium was underdeveloped in the glands of postnatal day 4 (PND 4) females exposed to TCDD. Specifically, there were significantly fewer primary branches from the nipple, slower migration through the fat pad, and fewer branches and terminal buds when compared to corn oil-treated controls. This delayed development was persistent following puberty, resulting in undifferentiated terminal end buds and spindly structures with few lateral branches or lobules. The mammary epithelium of 110 day old TCDD-exposed females possessed differentiated ends, yet failed to fill the fat pad resulting in sparse lobule formation. The critical time of TCDD exposure leading to stunted mammary gland development was examined by dosing timed-pregnant dams with 1 ug/kg (gavage) on gestation day (GD) 15 or 20, and PND 1, 3, 5, or 10. The glands of female pups were analyzed on PND 4 and 25. At both time points the only dose timing that triggered consistently underdeveloped epithelium was GD 15. Glands from a few of the animals exposed on GD 20 displayed sparse lateral branching. However, their migration through the fat pad, terminal alveolar bud formation and primary branching was similar to controls. Glands from all postnatal dosing times were also comparable to controls. Additionally, in the aforementioned studies, the GD 15 TCDD-exposed pups were significantly smaller on PND 4 and as adults than control animals (P<0.05). To determine if this was a nutritional/lactational effect of the dosing, a two-generational study was designed in which the offspring of the dosed dams (F1) were raised to 60 days of age and bred to confirmed breeder 90 day old Long Evans males. They and their offspring (F2) were assessed on GD14, PND 10 (lactational challenge), and at weaning. On GD 14, TCDD-exposed F1 females carried significantly fewer fetuses than those exposed to corn oil (13.4 vs. 16.6). Consistent with this observation, the TCDD-exposed F1 females had fewer live pups than controls on PND 4 (11.9 vs. 14.7). Interestingly, there was a pup sex bias in favor of females in the TCDD-exposed F1 group (0.36 vs. 0.51 in controls), and 47% of the F2 litters born to TCDD-exposed dams had greater than 66% of the litter as one sex (most were females). The mammary gland development of the F2 pups was examined. The majority of the F2 females of TCDD-exposed dams possessed mammary glands with either a branching or extension defect (many had both). However, the developmental defect was not as consistent as seen in the F1 generation. Finally, the lactational performance of the F1 dams was assessed on PND10. Dams were removed from their litters of 10 pups for 3 hours, pups were weighed and the dam returned. Pups were allowed to suckle for 30 minutes, the dam was removed and pups weighed again. The time it took for the dam to nest on the pups was also recorded. The amount of weight gain in F2 pups of TCDD-exposed dams was dramatically reduced when compared to controls (0.4 vs. 1.9 g/litter), whereas the amount of time it took the dams to settle on their pups was significantly increased (0:11 vs. 0:04 min.). In conclusion, the persistent delay in mammary gland development caused by TCDD exposure in utero leads to a lactational defect in F1 females and to fewer and smaller pups, an event that is probably not due solely to the lactational defect. The effect of TCDD exposure carries over into the F2 generation, adversely affecting mammary gland development.