Urinary cadmium and risk of breast cancer

描述(申请人提供)：镉是一种自然存在于环境中的重金属。除了土壤中的自然含量外，从20世纪下半叶开始，在农田中增加磷肥和污水污泥的使用，导致食品和烟草中的镉含量增加，使其获得了“绿色革命的特洛伊木马”的恶名。从历史上看，镉健康研究的重点是在小群体中高暴露对健康的影响。然而，过去十年积累的流行病学和机械学证据表明，低水平、长期接触镉会带来广泛的健康风险，包括内分泌中断和乳腺癌和子宫内膜癌风险增加，以及生殖影响、骨质疏松、肾功能、心血管疾病和牙周病。重要的是，早期的流行病学和机械学证据表明，在30%-60%的人口中常见的暴露水平可能会观察到风险增加，这强调了对低水平镉的影响进行重点研究的必要性。这项竞争性修订申请建议在母项目的基础上创建一个镉联盟：一项前瞻性病例队列流行病学研究，旨在检验镉导致西方人群乳腺癌高发的假设。拟议的联合体将加强母项目，同时本身提供新的发现，这些发现将指导未来对镉暴露风险评估的研究和临床应用。一个目标是调查尿镉水平的时间变异性。这种生物标志物有望成为数十年暴露的罕见长期指标；然而，在低暴露人群中进行验证研究是必要的，以评估单个现场尿样是否是对人体镉负荷的稳定、可重复性的估计。第二个目标是开发分子生物标记物，考虑到镉、锌和金属硫蛋白之间的相互作用，帮助确定接触的生物终点和可能与致癌过程的联系。第三个目标将研究DNA甲基化及其与乳腺癌和镉的关系，使这项研究成为首批表观遗传标记和癌症的前瞻性研究之一，并成为首批研究镉在人类群体表观遗传过程中的作用的研究之一。这个新的联盟将利用暴露科学、表观遗传学、生化分析和生物标记物方面的进展，将人口水平和分子水平的努力联系起来，为理解镉的健康风险带来新的见解。值得注意的是，通过更广泛的监管来避免人群接触镉，疾病预防的潜力很大，因为普通人群接触镉的主要来源，如化肥，已经得到很好的认识。

DESCRIPTION (provided by applicant): Cadmium is a heavy metal that occurs naturally in the environment. In addition to the natural levels in soil, increased application of phosphate fertilizers and sewage sludge to cropland beginning in the latter half of the late 20th century resulted in increased cadmium in foodstuffs and tobacco, earning it notoriety as "the Trojan horse of the green revolution". Historically, cadmium-health research has focused on health effects from high exposures occurring in small subpopulations. However, epidemiologic and mechanistic evidence accumulated during the past decade suggests widespread health risks from low-level, chronic exposure to cadmium, including endocrine disruption and increased risk for breast and endometrial cancer along with reproductive effects, osteoporosis, renal function, cardiovascular disease and periodontal disease. Importantly, the early epidemiologic and mechanistic evidence suggests that increased risk may be observed at levels of exposure common to 30-60% of the population, which emphasizes the need for focused research on the effects of low-level cadmium. This competitive revision application proposes the creation of a cadmium consortium that builds onto the parent project: a prospective case-cohort epidemiologic study designed to test the hypothesis that cadmium contributes to the high incidence of breast cancer in Western populations. The proposed consortium will enhance the parent project while providing novel findings in its own right, findings that will guide future studies and clinical application of risk assessment for cadmium exposure. One aim will investigate temporal variability in urinary cadmium levels. This biomarker has the promise of being a rare long-term indicator of decades-long exposure; however, validation studies in lower-exposure populations, such as those in the U.S., are necessary to assess whether a single spot urine sample is a stable, reproducible estimate of cadmium body burden. A second aim will develop molecular biomarkers to help identify biological endpoints of exposure and possible connections to the carcinogenic process, considering interplay between cadmium, zinc, and metallothionein. A third aim will investigate DNA methylation profiles and their association with breast cancer and cadmium, making this one of the first prospective studies of epigenetic markers and cancer, and one of the first to examine cadmium's role in epigenetic processes in a human population. This new consortium will bridge population-level and molecular efforts to bring novel insights to the understanding of health risks from cadmium, using advances in exposure science, epigenetics, biochemical analysis, and biomarkers. Of note, there is great potential for disease prevention, with more extensive regulation to avoid population exposure, because primary sources of exposure to cadmium for the general population, e.g., fertilizer, are already well recognized.