Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Environ Health. 2011 Jan 17;10(1):5. doi: 10.1186/1476-069X-10-5.
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.
环境雌激素是外源性雌激素模拟化合物，可干扰内源性内分泌系统。这些内分泌干扰物中的几种已被证明会改变正常发育并影响实验模型中的肿瘤发生。邻苯二甲酸丁基苄基酯（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。本研究旨在阐明产前暴露于 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 天到分娩，通过灌胃向怀孕的 Sprague Dawley CD 大鼠给予 120mg 或 500mg BBP/kg/天的剂量，进行宫内暴露。在 21、35、50 和 100 天时处死雌性幼崽。通过全乳培养和 BrdU 掺入分别研究乳腺的形态和增殖指数。通过微阵列评估基因表达谱。通过实时 RT-PCR 进一步验证了几个发现差异表达并与不同功能类别相关的基因。
BBP 的产前暴露导致阴道开口延迟，并在治疗结束后很长时间（主要在 35 天）改变了产后乳腺。高剂量暴露导致乳腺结构和增殖指数发生改变，主要影响未分化的末端芽。此外，暴露大鼠的这种腺体的表达谱以剂量依赖的方式发生改变。功能类别分析表明，修饰的基因与免疫功能、细胞信号转导、增殖和分化或代谢有关。
我们的数据表明，BBP 的宫内暴露导致青春期延迟和乳腺形态改变。这些变化伴随着先前与致癌易感性增加相关的基因表达的改变。
