Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106-4965, USA.
Biol Reprod. 2011 Sep;85(3):490-7. doi: 10.1095/biolreprod.110.090431. Epub 2011 Jun 2.
Bisphenol A (BPA) is an industrial plasticizer that leaches from food containers during normal usage, leading to human exposure. Early and chronic exposure to endocrine-disrupting environmental contaminants such as BPA elevates the potential for long-term health consequences. We examined the impact of BPA exposure on fetal programming of mammary tumor susceptibility as well as its growth promoting effects on transformed breast cancer cells in vivo. Fetal mice were exposed to 0, 25, or 250 μg/kg BPA by oral gavage of pregnant dams. Offspring were subsequently treated with the known mammary carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). While no significant differences in postnatal mammary development were observed, both low- and high-dose BPA cohorts had a statistically significant increase in susceptibility to DMBA-induced tumors compared to vehicle-treated controls. To determine if BPA also promotes established tumor growth, MCF-7 human breast cancer cells were subcutaneously injected into flanks of ovariectomized NCR nu/nu female mice treated with BPA, 17beta-estradiol, or placebo alone or combined with tamoxifen. Both estradiol- and BPA-treated cohorts formed tumors by 7 wk post-transplantation, while no tumors were detected in the placebo cohort. Tamoxifen reversed the effects of estradiol and BPA. We conclude that BPA may increase mammary tumorigenesis through at least two mechanisms: molecular alteration of fetal glands without associated morphological changes and direct promotion of estrogen-dependent tumor cell growth. Both results indicate that exposure to BPA during various biological states increases the risk of developing mammary cancer in mice.
双酚 A（BPA）是一种工业增塑剂，在正常使用过程中会从食品容器中渗出，导致人体暴露。早期和慢性暴露于内分泌干扰环境污染物如 BPA 会增加长期健康后果的可能性。我们研究了 BPA 暴露对乳腺肿瘤易感性的胎儿编程以及其对体内转化乳腺癌细胞的生长促进作用的影响。通过口服灌胃给怀孕的母鼠暴露于 0、25 或 250μg/kg 的 BPA，胎儿小鼠。随后，后代用已知的乳腺致癌剂 7,12-二甲基苯并[a]蒽（DMBA）处理。虽然在产后乳腺发育方面没有观察到显著差异，但低剂量和高剂量 BPA 组与载体处理对照组相比，对 DMBA 诱导的肿瘤的易感性均有统计学显著增加。为了确定 BPA 是否也促进已建立的肿瘤生长，将 MCF-7 人乳腺癌细胞皮下注射到接受 BPA、17β-雌二醇或安慰剂单独或与他莫昔芬联合治疗的卵巢切除 NCR nu/nu 雌性小鼠的侧腹。在移植后 7 周，雌二醇和 BPA 处理组均形成肿瘤，而安慰剂组未检测到肿瘤。他莫昔芬逆转了雌二醇和 BPA 的作用。我们得出结论，BPA 可能通过至少两种机制增加乳腺肿瘤发生：胎儿腺体的分子改变而不伴有形态变化，以及直接促进雌激素依赖性肿瘤细胞生长。这两个结果都表明，在各种生物学状态下暴露于 BPA 会增加小鼠患乳腺癌的风险。
