In utero dietary exposure to endocrine disruptors

描述(由申请人提供)：在人类和啮齿动物模型中，子宫激素环境的升高可能会增加日后患乳腺癌的易感性。我们的目标一直是确定饮食成分，当喂给怀孕的大鼠母鼠时，会减少雌性后代的乳腺肿瘤发生。因此，我们喂给怀孕的大鼠亚麻籽饮食，其中含有木脂素、亚麻酚(SDG)、n-3多不饱和脂肪酸(PUFAs)和纤维，所有这些都与降低乳腺癌风险有关，并可能降低血清雌激素。然而，我们发现孕期饲喂10%亚麻籽饲料或15%脱脂亚麻籽饲料的母鼠的雌性后代患DMBA诱导的乳腺肿瘤的风险增加。这是令人惊讶的，因为他们的乳腺含有较少的恶性转化目标(末端芽，TEB)，其他研究人员也报道了这一点。亚麻籽的蛋白质成分积累的重金属镉含量超过了世界卫生组织规定的最高标准。由于镉是一种内分泌干扰物，并激活雌激素受体，它还会损害修复DMA损伤的能力，因此我们假设，在子宫内接触亚麻籽中的镉会增加日后患乳腺癌的风险。我们的研究有以下具体目的：(1)确定子宫内镉暴露是否会增加乳腺癌的发生；(2)确定木脂素SDG、脂肪酸n-3PUFA或纤维的存在是否改变了宫内镉暴露对乳腺肿瘤发生的影响；以及(3)比较子宫内暴露于亚麻籽、镉或镉、SDG、n-3PUFA和纤维组合的大鼠DMA损伤修复的变化，包括抑癌基因Brcal和P53的表达，以及雌激素诱导的信号转导通路。饲料中SDG、n-3多不饱和脂肪酸和纤维的水平将与10%亚麻籽饲料中的水平相似。我们将使用的模型系统是暴露在致癌物质DMBA中的Spraogue Dawley大鼠，这种致癌物质导致的乳腺肿瘤在生物学上与人类乳腺癌相似。这项研究的结果将为在子宫内暴露于亚麻籽可以改变日后发生乳腺肿瘤的易感性的机制提供深入的见解。特别是，我们将确定在子宫内暴露于亚麻籽中高水平的镉是否是关键的中介因素，以及亚麻籽/镉的影响是否涉及雌激素受体信号的变化或氧化损伤修复，或两者兼而有之。

DESCRIPTION (provided by applicant): Elevated in utero hormonal environment may increase later susceptibility to develop breast cancer, both in human and rodent models. Our goal has been to identify dietary components that, when fed to pregnant rat dams, results a reduced mammary tumorigenesis among female offspring. Thus, we fed pregnant rats flaxseed diet that contains lignan secoisolariciresinol (SDG), n-3 polyunsaturated fatty acids (PUFAs) and fiber, all that have been linked to reduced breast cancer risk and that potentially reduce serum estrogens. However, we found that female offspring of dams fed 10% flaxseed diet or 15% defatted flaxseed diet during pregnancy were at an increased risk of developing DMBA-induced mammary tumors. This was surprising since their mammary glands contained less targets (terminal end buds, TEBs) for malignant transformation, as also reported by other investigators. The protein component of flaxseed accumulates heavy metal cadmium to the levels exceeding the maximum guidelines set by the World Health Organization. Since cadmium is an endocrine disrupter and activates the estrogen receptor, and it also impairs the ability to repair DMA damage, we hypothesize that in utero exposure to cadmium in flaxseed increases later breast cancer risk. Our study has the following specific aims: (1) determine whether in utero cadmium exposure increases later mammary tumorigenesis; (2) determine whether the presence of lignan SDG, fatty acid n-3 PUFA or fiber modify the effects of in utero cadmium exposure on mammary tumorigenesis; and (3) compare changes in DMA damage repair, including expression of tumor suppressor genes Brcal and p53, and estrogen-induced signaling pathways in rats exposed to flaxseed, cadmium or a combination of cadmium, SDG, n-3 PUFA and fiber in utero. Dietary levels of SDG, n-3 PUFA and fiber will be similar to those present in 10% flaxseed diet. The model system we will use is Sprague Dawley rat exposed to carcinogen DMBA that results mammary tumors that are biologically similar to human breast cancers. Results obtained in this study will provide insight into the mechanisms by which in utero exposure to flaxseed can alter later susceptibility to develop mammary tumors. In particular, we will determine whether in utero exposure to cadmium present at high levels in flaxseed, is the key mediating factor, and whether flaxseed/cadmium's effects involve changes in estrogen receptor signaling or oxidative damage repair or both.