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，子宫激素环境升高可能会增加后期患乳腺癌的易感性。我们的目标是确定饮食成分，当给怀孕的大鼠喂食时，会减少雌性后代的乳腺肿瘤发生。因此，我们给怀孕的大鼠喂食含有木脂素、异脂树脂醇（SDG）、n-3多不饱和脂肪酸（PUFAs）和纤维的亚麻籽饮食，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，我们发现在怀孕期间饲喂10%亚麻籽饲料或15%脱脂亚麻籽饲料的雌性后代患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（终末芽，teb），其他研究者也报道过。亚麻籽的蛋白质成分积累重金属镉的水平超过了世界卫生组织设定的最大指导方针。由于镉是一种内分泌干扰物，可以激活雌激素受体，并且还会损害修复DMA损伤的能力，我们假设在子宫内接触亚麻籽中的镉会增加后来患乳腺癌的风险。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晚期乳腺肿瘤的发生；(2)确定木脂素SDG、脂肪酸n-3 PUFA或纤维的存在是否会改变子宫内镉暴露对乳腺肿瘤发生的影响；(3)比较子宫内暴露于亚麻籽、镉或镉、SDG、n-3 PUFA和纤维组合的大鼠在DMA损伤修复中的变化，包括肿瘤抑制基因Brcal和p53的表达，以及雌激素诱导的信号通路。膳食中SDG、n-3 PUFA和纤维的含量与10%亚麻籽饮食中的含量相似。我们将使用的模型系统是暴露于致癌物DMBA的斯普拉格·道利大鼠，这种致癌物会导致与人类乳腺癌相似的乳腺肿瘤。本研究获得的结果将为子宫内暴露于亚麻籽可以改变乳腺肿瘤后期易感性的机制提供见解。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或氧化损伤修复的变化或两者兼而有之。

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.