Jenkins Sarah, Raghuraman Nandini, Eltoum Isam, Carpenter Mark, Russo Jose, Lamartiniere Coral A
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Environ Health Perspect. 2009 Jun;117(6):910-5. doi: 10.1289/ehp.11751. Epub 2009 Jan 7.
Bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles.
Based on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer.
We exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 mug BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age.
The combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days postpartum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1-3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age.
The data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1-3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure.
双酚A（BPA）广泛用于制造聚碳酸酯塑料，包括婴儿配方奶粉瓶。
基于该多酚类物质已报道的内分泌干扰活性，我们推测生命早期暴露于双酚A会引发乳腺组织的发育变化，并导致乳腺癌易感性增加。
我们通过给哺乳母鼠口服0、25和250微克双酚A/千克体重/天，经泌乳使新生/青春期前大鼠暴露于双酚A。对于肿瘤发生研究，雌性后代在50日龄时暴露于30毫克二甲基苯并蒽（DMBA）/千克体重。
与对照组相比，DMBA处理与泌乳期暴露于双酚A的联合作用显示乳腺肿瘤多样性呈剂量依赖性增加，且肿瘤潜伏期缩短。在无DMBA处理的情况下，泌乳期双酚A暴露导致产后50天而非21天（最后一次双酚A处理后不久）细胞增殖增加和细胞凋亡减少。通过蛋白质印迹分析，我们确定类固醇受体辅激活因子（SRCs）1 - 3、Akt、磷酸化Akt、孕激素受体A（PR - A）和erbB3蛋白在50日龄时显著上调。
此处呈现的数据提供了首个证据，即在DMBA诱导的啮齿动物乳腺癌模型中，母体在泌乳期暴露于双酚A会增加乳腺癌发生。PR - A、SRC 1 - 3、erbB3和Akt活性的变化与细胞增殖增加和细胞凋亡减少在乳腺癌易感性中起作用一致。这些改变解释了泌乳期双酚A暴露后乳腺癌发生增强的现象。
