Impact of environmental metal/metalloid exposures on mammographic breast density, a marker of breast cancer

环境金属/类金属暴露对乳房 X 光检查乳腺密度（乳腺癌标志物）的影响

• 批准号: 9765326
• 负责人: CELIA BYRNE
• 金额: $ 87.95万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765326
• 关键词: Address; Affinity; Animal Model; Binding; Biological Markers; Breast; Calcium; Cations; Communities; Data; Disease; Environmental Exposure; Environmental Impact; Environmental Pollution; Epidemic; Epidermal Growth Factor; Estradiol; Estrogen Receptor alpha; Estrogens; Exposure to; Focus Groups; Food; Gene Expression; Genes; Genetic Polymorphism; Hormone replacement therapy; Hormones; In Vitro; Incidence; Insulin-Like Growth Factor I; Laboratories; Ligand Binding Domain; Ligands; Maintenance; Malignant Neoplasms; Mammary gland; Mammographic Density; Medically Underserved Area; Menopause; Metal exposure; Metals; Morphology; Nitrites; Participant; Pathway interactions; Physiological; Progesterone; Progestins; Publishing; Risk; Single Nucleotide Polymorphism; Stem cells; Surveys; Testing; Translating; Variant; Washington; Water; Woman; Work; breast density; density; falls; high risk; in vitro Assay; in vivo; malignant breast neoplasm; progesterone receptor B; public health relevance; receptor; response

 DESCRIPTION (provided by applicant):Residents in medically underserved areas of Washington, DC have express the concern that the high incidence of cancer in their community is due to contaminants in their food and water, including metals. Results from our laboratory and others show that environmentally relevant amounts of specific metals and metalloids, referred to as metalloestrogens, activate estrogen receptor-alpha (ERα) in vitro and in vivo through a high affinity interaction with the ligand binding domain (LBD) of the receptor. These metals and metalloids fall into two separate subclasses, bivalent cations and oxyanions. New results from our laboratory suggest that metalloestrogens also activate progesterone receptor-B (PR-B). The ability to activate ERα, and potentially PR-B suggests that environmental exposure to metals and metalloids with estrogen- and progestin-like activity may increase the risk of developing breast cancer. In response to the concerns of the community, this application will address the question whether exposure to metals and metalloids increases the risk of developing breast cancer by testing the hypothesis that higher lifetime environmental exposure to metals and metalloids with estrogen- and progesterone-like activity is associated with higher mammographic density in women during the menopausal transition and delays or reduces the involution of mammary gland and the decline in mammographic breast density during this period. Aim 1 will determine whether metals and metalloids mimic the effects of estrogens and progestin on mammary gland morphology, stem and progenitor cells, and gene expression in a menopausal animal model (Aim 1a) and define the mechanisms by which metals and metalloids activate PR-B in in vitro assays (Aim 1b). Aim 2 will determine whether environmental exposure to metallohormones is associated with changes in breast density through the menopausal transition and define the mechanism by which metals and metalloids alter breast density. Specifically, Aim 2 will establish if: a, higher metallohormone levels are associated with increased mammographic density; b, higher metallohormone levels are associated with maintenance of higher breast density through the menopausal transition; and c, polymorphisms in the calcium pathway are associated with increased mammographic breast density indicating the mechanism through which bivalent cationic metallohormones increase risk. To accomplish these aims, we will continue to engage with our partners to get their input, to help collect data, and to translate and communicate the scientific findings to the community.

 描述(申请人提供)：华盛顿特区医疗服务不足地区的居民表示，他们社区癌症的高发病率是由于他们的食物和水中的污染物，包括金属。我们实验室和其他实验室的结果表明，环境相关数量的特定金属和类金属，称为金属雌激素，通过与受体的配体结合结构域的高亲和力相互作用，在体外和体内激活雌激素受体-α(ERα)。这些金属和类金属分为两个不同的子类，即二价阳离子和氧阴离子。我们实验室的新结果表明，金属雌激素也激活孕激素受体B(PR-B)。激活ER-α和潜在的PR-B的能力表明，环境中暴露于具有雌激素和孕激素样活性的金属和金属可能会增加患乳腺癌的风险。为回应社会人士的关注，这项申请将测试以下假设，即终身接触具有雌激素和黄体酮类活性的金属和金属会与更年期妇女较高的乳房摄影密度有关，并延缓或减少乳腺退化和乳房摄影密度的下降，从而解决暴露于金属和类金属是否会增加患乳腺癌的风险的问题。目的1在更年期动物模型中确定金属和类金属是否模拟雌激素和孕激素对乳腺形态、干细胞和祖细胞以及基因表达的影响(目标1a)，并在体外实验中确定金属和类金属激活PR-B的机制(目标1b)。目的2将确定环境中暴露于金属激素是否与绝经过渡期间乳房密度的变化有关，并确定金属和类金属改变乳房密度的机制。具体地说，AIM 2将确定：a，较高的金属激素水平是否与乳房X光摄影密度增加相关；b，较高的金属激素水平与在绝经过渡期间保持较高的乳房密度有关；c，钙途径的多态与乳房X光摄影密度的增加相关，这表明二价阳离子金属激素增加风险的机制。为了实现这些目标，我们将继续与我们的合作伙伴合作，收集他们的意见，帮助收集数据，并将科学发现翻译和传达给社会。

项目成果

Serum concentrations of DDE, PCBs, and other persistent organic pollutants and mammographic breast density in Triana, Alabama, a highly exposed population.

阿拉巴马州特里亚纳（阿拉巴马州特里亚纳）高度暴露人群中 DDE、PCB 和其他持久性有机污染物的血清浓度以及乳腺 X 光检查密度。

• DOI: 10.1016/j.envres.2019.109068
• 发表时间: 2020
• 期刊: Environmental research
• 影响因子: 8.3
• 作者: Rusiecki,JA;Denic-Roberts,H;Byrne,C;Cash,J;Raines,CF;Brinton,LA;Zahm,SH;Mason,T;Bonner,MR;Blair,A;Hoover,R
• 通讯作者: Hoover,R