In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats.
In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats.
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DOI：
10.1186/1476-069x-10-5
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发表时间：
2011-01-17
期刊：
影响因子：
--
通讯作者：
Russo J
中科院分区：
文献类型：
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作者：
Moral R;Santucci-Pereira J;Wang R;Russo IH;Lamartiniere CA;Russo J
环境雌激素是外源性的雌激素样化合物，可以干扰内源性内分泌系统。在实验模型中，其中几种内分泌干扰物已被证明会改变正常发育并影响肿瘤发生。邻苯二甲酸正丁基苄酯（BBP）是一种广泛使用的增塑剂，是一种众所周知的内分泌干扰物。本研究的目的是阐明产前暴露于BBP对不同年龄大鼠乳腺形态、增殖指数和基因组特征的影响。从受孕后第10天至分娩，通过对妊娠Sprague道利CD大鼠灌胃120 mg或500 mg BBP/kg/天进行子宫内暴露。在第21、35、50和100天对雌性窝仔实施安乐死。分别从整体包埋法和BrdU掺入法研究乳腺的形态学和增殖指数。基因表达谱通过微阵列进行评估。通过真实的时间RT-PCR进一步验证了发现的差异表达和与不同功能类别相关的几个基因。出生前暴露于BBP会导致阴道张开延迟，并在治疗结束后很长时间内（主要是35日龄）出现出生后乳腺变化。暴露于高剂量导致乳腺结构和增殖指数改变，主要影响未分化的末端芽。此外，在暴露的大鼠中，该腺体的表达谱以剂量依赖的方式被修改。功能类别分析表明，修饰的基因与免疫功能、细胞信号传导、增殖和分化或代谢有关。我们的数据表明，在子宫内暴露于BBP诱导延迟青春期发病和修改乳腺形态。这些改变伴随着先前与致癌易感性增加相关的基因表达的修饰。
Environmental estrogens are exogenous estrogen-mimicking compounds that can interfere with endogenous endocrine systems. Several of these endocrine disruptors have been shown to alter normal development and influence tumorigenesis in experimental models. N-butyl benzyl phthalate (BBP), a widely used plasticizer, is a well-known endocrine disruptor. The aim of this study was to elucidate the effect of prenatal exposure to BBP on the morphology, proliferative index, and genomic signature of the rat mammary gland at different ages. In utero exposure was performed by gavage of pregnant Sprague Dawley CD rats with 120mg or 500mg BBP/kg/day from day 10 post-conception to delivery. Female litters were euthanized at 21, 35, 50 and 100 days. The morphology and proliferative index of the mammary gland were studied from whole mount preparations and BrdU incorporation, respectively. Gene expression profile was assessed by microarrays. Several genes found differentially expressed and related to different functional categories were further validated by real time RT-PCR. Prenatal exposure of BBP induced delayed vaginal opening and changes in the post-natal mammary gland long after the end of the treatment, mainly by 35 days of age. Exposure to the high dose resulted in modifications in architecture and proliferative index of the mammary gland, mostly affecting the undifferentiated terminal end buds. Moreover, the expression profiles of this gland in the exposed rats were modified in a dose-dependent fashion. Analysis of functional categories showed that modified genes were related to immune function, cell signaling, proliferation and differentiation, or metabolism. Our data suggest that in utero exposure to BBP induced a delayed pubertal onset and modified morphology of the mammary gland. These alterations were accompanied by modifications in gene expression previously associated with an increased susceptibility to carcinogenesis.