In utero dietary exposure to endocrine disruptors

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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.