In utero dietary exposure to endocrine disruptors

子宫内饮食接触内分泌干扰物

• 批准号: 6940954
• 负责人: LEENA A. HILAKIVI-CLARKE
• 金额: $ 15.52万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6940954
• 关键词: DNA repair; brca gene; breast neoplasms; cadmium; cancer risk; carcinogenesis; developmental nutrition; dietary fiber; dietary mineral; dietary supplements; embryo /fetus toxicology; female; hormone related neoplasm /cancer; laboratory rat; nutrition related tag; p53 gene /protein; pathogenic diet; unsaturated fatty acids

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.

描述（由申请人提供）：子宫荷尔蒙环境中的升高可能会增加以后在人类和啮齿动物模型中发展乳腺癌的易感性。我们的目标是确定饮食成分，当喂给怀孕的大鼠大坝时，雌性后代的乳腺肿瘤发生减少。因此，我们喂了含有木质蛋白脱糖酸糖尿醇（SDG），N-3多不饱和脂肪酸（PUFAS）和纤维的怀孕大鼠亚麻籽饮食，所有这些饮食与乳腺癌降低以及可能降低血清雌激素有关。但是，我们发现，在怀孕期间，喂食10％亚麻籽饮食或15％defatted亚麻籽饮食的大坝后代的风险增加了DMBA诱导的乳腺肿瘤的风险。这是令人惊讶的，因为它们的乳腺包含的靶标（终端芽，tebs，tebs）较少，正如其他研究者所报道的那样。亚麻籽的蛋白质成分将重金属镉累积到超过世界卫生组织设定的最大准则的水平。由于镉是一种内分泌剂并激活雌激素受体，并且也损害了修复DMA损伤的能力，因此我们假设在亚麻籽中可能会暴露于子宫内，会增加后来的乳腺癌风险。我们的研究具有以下特定目的：（1）确定在子宫内暴露中是否会增加后来的乳腺肿瘤发生； （2）确定是否存在木质脂肪酸，脂肪酸N-3 PUFA或纤维是否会改变子宫镉暴露对乳腺肿瘤发生的影响； （3）比较DMA损伤修复的变化，包括抑制肿瘤基因BRCAL和p53的表达，以及暴露于亚麻籽的大鼠中雌激素诱导的信号通路。饮食水平的可持续发展目标，N-3 PUFA和纤维将与10％亚麻籽饮食中存在的饮食水平相似。我们将使用的模型系统是暴露于致癌DMBA的sprague dawley大鼠，导致乳腺肿瘤在生物学上与人类乳腺癌相似。在这项研究中获得的结果将提供有关子宫内暴露于亚麻籽的机制可以改变后来发展乳腺肿瘤的机制。特别是，我们将确定在子宫内暴露于亚麻籽中的镉中是否是关键的中介因子，以及亚麻籽/镉的效应是否涉及雌激素受体信号传导或氧化损伤修复的变化，还是两者兼而有之。