Influence of Diet, Iron Stores, and Toxic Metals on Uptakes and Effects on Uterine Fibroid Risk in African American Women

项目摘要/摘要 普通人群长期接触低剂量有毒金属，包括铅、镉和 来自受污染的食物和饮用水的锰在美国很普遍，在非洲 美国人比他们的白人同龄人暴露得更多。这种暴露的种族差异可能是 对非裔美国人经历的不平等的疾病负担，包括子宫发育 肌瘤。超过80%的非裔美国女性在年龄上会发生这些平滑肌子宫肿瘤。 50，并与相当大的发病率有关。目前已确定的这种疾病的风险因素很少 易于干预，促使有必要调查环境因素的作用。此外，给出了 避免接触环境中普遍存在的有毒金属的困难，理解 行为和生物因素，包括饮食和铁储存，参与人体对这些化学物质的吸收 对预防至关重要。然而，很少有关于这些因素的人体研究，这些因素可能 影响有毒金属的吸收和吸收，特别是在育龄妇女中，大多数 他们中有铁、锌和钙摄入量不足的人，对他们来说，月经失血是一种 是缺铁的主要原因。此外，先前对金属和子宫肌瘤的人体研究也取得了成果。 相互矛盾的结果，可能是由于所采用的研究设计的局限性。这其中的中心假设 建议是：1)日常饮食中铁、钙、锌的摄入量普遍不足， 由于大量月经出血而消耗体内的铁，增加身体对铅、镉和铅的摄取。 2)这些有毒金属会增加子宫肌瘤的风险，因为 体内和体外均表现出激素作用。为了检验这些假设，拟议的研究将建立在 一个由近1700名年轻的非裔美国女性组成的队列，使用数据和存档的生物样本 来自环境、生活方式和肌瘤研究(SELF)，一项为期5年的肌瘤前瞻性研究，由 国家环境健康科学研究所(ZIAES049013，D.Baird，首席研究员)。 来自注册的存档全血样本将被分析铅、镉和锰，并存储 将对血清样本进行体内铁储存、铁蛋白和转铁蛋白受体生物标记物的测量。这些 生物标志物数据将与关于饮食摄入量和大量月经出血的问卷数据以及 在5年内每20个月收集一次子宫肌瘤的超声数据，以实现以下目标：1) 确定膳食中基本营养素铁、钙和锌的摄入量不足的程度 与血液中铅、镉和锰浓度的变化有关；2)确定 体内铁贮存量低、月经大量出血与铅、镉和锰之间的关系 浓度；以及3)确定血铅、镉和锰之间的关系 登记时的浓度和5年内子宫肌瘤的发病率。 美国国立卫生研究院独立之路中提出的研究和伴随职业发展计划 获奖申请将允许厄普森医生实现她作为护士科学家的长期职业目标来回答 将妇女生殖健康和环境健康领域联系起来的重要研究问题 最终提供可行的干预措施，以改善育龄妇女的健康。K99在指导下- 该奖项的阶段将在美国国立理工学院的内部研究计划内进行。 环境健康科学研究所，是环境健康研究的先锋。厄普森医生会 接受子宫肌瘤著名学者唐娜·贝尔德、珍妮特·霍尔和埃里克·托卡尔博士的指导 分别是研究、生殖内分泌学和金属毒理学。其他指导将是 由她的顾问委员会提供，该委员会由营养流行病学专家米歇尔·门德斯博士组成， 伊丽莎白·科文博士，她在R01助学金和学术求职过程方面拥有专业知识 一位著名的护士科学家。指导部分将得到有组织的培训的补充 活动，包括课程作业、定向阅读、参加研讨会、研讨会和国家 会议和职业发展活动，以解决专业成长的关键领域，将促进 向独立过渡。从提供这种指导和完成有组织的培训 活动，厄普森博士将实现她的短期目标，包括精通毒物学， 生殖内分泌学和营养学，并将这些知识整合到她现有的护理知识中 和流行病学技能，以便在K99和R00奖项阶段进行新的研究。这 将使厄普森博士能够提供有关人体行为和生物因素的关键信息 对有毒金属和子宫肌瘤风险进行首次前瞻性研究。 R00独立阶段。进行这项创新的研究和培训不仅将促进 成功启动了候选人作为护士科学家的独立研究生涯，但将为未来提供信息 预防不同程度接触有毒金属、减轻疾病负担和提高质量的干预措施 与国家护理研究所的研究优先事项保持一致。

PROJECT SUMMARY/ABSTRACT Chronic exposure of the general population to low-doses of toxic metals, including lead, cadmium, and manganese, from contaminated food and drinking water is widespread in the United States, with African Americans being more exposed than their white counterparts. This racial disparity in exposure may contribute to the unequal burden of disease experienced by African Americans, including the development of uterine fibroids. These smooth muscle uterine tumors develop in more than 80% of African American women by age 50 and are associated with substantial morbidity. Few risk factors for this disease have been identified that are amenable to intervention, motivating the need to investigate the role of environmental factors. In addition, given the difficulty in avoiding exposure to toxic metals that are ubiquitous in the environment, understanding behavioral and biologic factors, including diet and iron stores, involved in the body's uptake of these chemicals is critical for prevention. However, few human studies have been conducted on these factors that may influence the uptake and absorption of toxic metals, particularly among reproductive-age women, the majority of whom have inadequate dietary intakes of iron, zinc, and calcium, and for whom menstrual blood loss is a major contributor to iron deficiency. In addition, prior human studies of metals and uterine fibroids have yielded contradictory results, likely due to the limitations of the study designs employed. The central hypotheses in this proposal are that 1) common deficiencies in the dietary intake of iron, calcium, and zinc as well as the depletion of iron stores from heavy menstrual bleeding, increase the body's uptake of lead, cadmium and manganese in women, and 2) these toxic metals increase uterine fibroid risk given the mutagenic and hormonal actions exhibited in vivo and in vitro. To test these hypotheses, the proposed research will build on an established cohort of nearly 1,700 young, African American women using data and archived biosamples from the Study of Environment, Lifestyle & Fibroids (SELF), a 5-year prospective study of fibroids funded by the National Institute of Environmental Health Sciences (ZIAES049013, D. Baird, Principal Investigator). Archived whole blood samples from enrollment will be analyzed for lead, cadmium, and manganese and stored serum samples will be measured for biomarkers of body iron stores, ferritin and transferrin receptor. These biomarker data will be linked to questionnaire data on dietary intake and heavy menstrual bleeding as well as to ultrasound data on fibroids collected every 20 months over 5 years to accomplish the following aims: 1) to determine the extent to which deficiencies in dietary intake of essential nutrients iron, calcium, and zinc are associated with altered blood concentrations of lead, cadmium, and manganese; 2) to determine the associations between low body iron stores, heavy menstrual bleeding, and lead, cadmium, and manganese concentrations; and 3) to determine the associations between blood lead, cadmium, and manganese concentrations at enrollment and uterine fibroid incidence over a 5-year period. The research and accompanying career development plan proposed in this NIH Pathway to Independence Award application will allow Dr. Upson to achieve her long-term career goal as a nurse scientist to answer important research questions that bridge the fields of women's reproductive health and environmental health to ultimately inform feasible interventions to improve the health of reproductive-age women. The K99 mentored- phase of the award will take place within the Intramural Research Program at the National Institute of Environmental Health Sciences, an institute at the vanguard of environmental health research. Dr. Upson will receive mentorship from Drs. Donna Baird, Janet Hall, and Erik Tokar, eminent scholars in uterine fibroid research, reproductive endocrinology, and metals toxicology, respectively. Additional mentoring will be provided by her advisory committee consisting of Dr. Michelle Mendez, an expert in nutritional epidemiology, and Dr. Elizabeth Corwin, who has expertise in R01 grantsmanship and the academic job search process as an established nurse scientist. The mentorship component will be complemented by structured training activities, consisting of coursework, directed readings, attendance at workshops, seminars, and national meetings, and career development activities to address key areas of professional growth that will promote the transition to independence. From the provision of this mentorship and the completion of structured training activities, Dr. Upson will achieve her short-term goals which include gaining a proficiency in toxicology, reproductive endocrinology, and nutrition, and integrating this knowledge into her existing nursing knowledge and epidemiologic skill set so as to conduct novel research during the K99 and R00 phases of the award. This will allow Dr. Upson to contribute critical information on behavioral and biologic factors involved in the body's uptake of metals as well to conduct the first prospective study of toxic metals and uterine fibroid risk during the R00 independent phase. The conduct of this innovative research and training will not only facilitate the successful launch of the candidate's independent research career as a nurse scientist, but will inform future interventions to prevent disparate exposure to toxic metals, reduce the burden of disease, and improve quality of life, in alignment with the research priorities of the National Institute of Nursing Research.