Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
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DOI：
10.1093/toxsci/67.1.63
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发表时间：
2002-05-01
影响因子：
3.8
通讯作者：
Youngblood, GL
中科院分区：
文献类型：
--
作者：
Fenton, SE;Hamm, JT;Youngblood, GL
妊娠期间接触2，3，7，8-四氯二苯并对二恶英（TCDD）已显示大鼠后代出现生殖异常，包括雌性乳房发育迟缓的不确定报告（Brown等人，1998，Carcinogenesis 19，1623-1629;刘易斯等人，2001年，毒理学。Sci. 62，46-53）。目前的研究旨在检查在子宫内和哺乳期暴露于TCDD的雌性后代乳腺发育，并确定这些影响的关键暴露期和细胞来源。Long-Evans大鼠在妊娠第15天（GD）暴露于1 μ g TCDD/kg体重（bw）或溶剂。在出生后第4、25、33、37、45和68天处死的TCDD暴露雌性动物的体重显著低于对照组同窝动物，青春期前后的动物表现出阴道开放延迟和持续的阴道线，但未显示出发情周期的改变。TCDD暴露动物的乳腺在PND 4表现出初级分支减少，上皮延长减少，肺泡芽和侧枝明显减少。这种现象持续到PND 68时，不像完全发达的腺体的控制，TCDD暴露大鼠保留未分化的终端结构。在妊娠第15天和第20天或哺乳期第1、3、5和10天暴露于TCDD或油的后代腺体在PND 4或25进行检查，以确定GD 15是持续抑制上皮发育的关键时期。使用乳腺上皮细胞移植的实验对照组和TCDD暴露的女性之间的建议，间质发挥了重要作用，在乳腺发育迟缓后，TCDD暴露。我们的数据表明，暴露于TCDD的乳房芽迁移到脂肪垫永久改变乳腺上皮细胞发育雌性大鼠后代。
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure during gestation has revealed reproductive anomalies in rat offspring, including inconclusive reports of stunted mammary development in females (Brown et al., 1998, Carcinogenesis 19, 1623-1629; Lewis et al., 2001, Toxicol. Sci. 62, 46-53). The current studies were designed to examine mammary-gland development in female offspring exposed in utero and lactationally to TCDD, and to determine a critical exposure period and cellular source of these effects. Long-Evans rats were exposed to 1 mug TCDD/kg body weight (bw) or vehicle on gestation day (GD) 15. TCDD-exposed females sacrificed on postnatal days (PND) 4, 25, 33, 37, 45, and 68 weighed significantly less than control litter mates, and peripubertal animals exhibited delayed vaginal opening and persistent vaginal threads, yet did not display altered estrous cyclicity. Mammary glands taken from TCDD-exposed animals on PND 4 demonstrated reduced primary branches, decreased epithelial elongation, and significantly fewer alveolar buds and lateral branches. This phenomenon persisted through PND 68 when, unlike fully developed glands of controls, TCDD-exposed rats retained undifferentiated terminal structures. Glands of offspring exposed to TCDD or oil on gestation days 15 and 20 or lactation days 1, 3, 5, and 10 were examined on PND 4 or 25 to discern that GD 15 was a critical period for consistent inhibition of epithelial development. Experiments using mammary epithelial transplantation between control and TCDD-exposed females suggested that the stroma plays a major role in the retarded development of the mammary gland following TCDD exposure. Our data suggest that exposure to TCDD prior to migration of the mammary bud into the fat pad permanently alters mammary epithelial development in female rat offspring.