Circulating levels of Persistent Organic Pollutants and Subclinical Atherosclerosis progression in Postmenopausal women

持久性有机污染物的循环水平和绝经后妇女亚临床动脉粥样硬化进展

• 批准号: 10707102
• 负责人: Zhanghua Chen
• 金额: $ 70.12万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707102
• 关键词: Adverse effects; Affect; Age; Archives; Atherosclerosis; Attention; Biological Markers; Body fat; Body mass index; CCL2 gene; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Carotid Atherosclerotic Disease; Categories; Cause of Death; Chemical Exposure; Chemicals; Cholesterol; Clinical Trials; Common carotid artery; Complex; Coronary Arteriosclerosis; Diet; Double-Blind Method; E-Selectin; Elderly; Endocrine; Environmental Exposure; Estradiol; Estrogens; Exercise; Exposure to; Fatty acid glycerol esters; Freezing; Functional disorder; Gene Expression; Glucose; Glycosylated hemoglobin A; Goals; Gonadal Steroid Hormones; Health; High Density Lipoprotein Cholesterol; Hormonal; Hormones; Human; Human body; IL6 gene; IL8 gene; Immune; Individual; Inflammation; Inflammatory; Insulin Resistance; Intercellular adhesion molecule 1; Interleukin-10; International; Intervention Trial; Joints; Knowledge; LDL Cholesterol Lipoproteins; Lipids; Lipoproteins; Long-Term Effects; Longitudinal Studies; Measurement; Measures; Menopausal Symptom; Menopause; Metabolic; Metabolic dysfunction; Morbidity - disease rate; Obesity; Older Population; Ovarian hormone; Oxidative Stress; P-Selectin; Pathologic; Pathology; Perimenopause; Pesticides; Physical activity; Physiological; Placebos; Plasma; Poly-fluoroalkyl substances; Polychlorinated Biphenyls; Population; Populations at Risk; Postmenopause; Proteins; Randomized; Receptor Signaling; Regulation; Reporting; Risk Factors; Role; Sampling; Smoking; Special Population; Subgroup; TNF gene; Toxic effect; Treatment Factor; Triglycerides; Ultrasonography; Unhealthy Diet; United States; VEGFA gene; Vascular Cell Adhesion Molecule-1; Visit; Whole Blood; Woman; Xenobiotics; arterial stiffness; bioaccumulation; cardiovascular disorder prevention; cardiovascular disorder risk; cardiovascular effects; cardiovascular health; carotid intima-media thickness; chemokine; cohort; cytokine; demographics; design; environmental chemical; experience; fasting glucose; high risk; high risk population; hormone therapy; intima media; intimal medial thickening; men; middle age; mortality; older men; older women; organochlorine pesticide; persistent organic pollutants; pollutant; polybrominated diphenyl ether; primary outcome; randomized, clinical trials; receptor; remediation; secondary outcome; smoking exposure; socioeconomics; trial design; ultrasound

ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in women in the US and globally. Menopausal transition poses remarkably elevated risk of CVD making postmenopausal women a population of special attention. There is an increasing concern about the exposure to environmental chemicals, particularly persistent organic pollutants (POPs), that disrupt human endocrine milieu and adversely affect cardiovascular health. The bioaccumulation of POPs over lifetime induces significant long-term health impact, especially among older population. However, the long-term effect of POPs on subclinical atherosclerosis progression, an early pathological feature of CVD, has not been studied well in postmenopausal women. In addition, the effect of POPs on atherosclerosis progression has not been evaluated in the US population. To our knowledge, no longitudinal study has been conducted to investigate the effects of POP mixtures and atherosclerosis progression. The only longitudinal study reporting an adverse effect of a specific class of POPs, per- and polyfluoroalkyl substances (PFASs), on increased carotid intima-media thickness (IMT, ultrasound) over 10 years was from a Swedish senior cohort. To fill the gaps in our understanding, we will investigate the long-term associations of plasma POPs concentrations and atherosclerosis progression in postmenopausal women in a unique cohort; Early vs Late Intervention Trial with Estradiol (ELITE) with 5-year longitudinal measurements of subclinical carotid atherosclerosis including gold-standard ultrasound measures (IMT, echogenicity, and stiffness) and frozen plasma samples to analyze absolute concentrations of 60 POPs from four main classes (polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), organochlorinated pesticides (OCPs), and (PFASs). ELITE is a randomized clinical trial including 596 early (<6years since menopause) and late (≥10years since menopause) postmenopausal women comparing rates of atherosclerosis progression over 5 years between women randomized to hormone therapy (HT) and placebo. Beyond the goal of investigating the effect of POP mixtures on atherosclerosis progression, we will investigate the impact of POP mixtures on risk factors of atherosclerosis including metabolic (lipids, glucose, HbA1c, and insulin resistance) and inflammatory biomarkers. Important covariates including the design factors (HT and placebo, early and late-postmenopausal groups), obesity, smoking, diet, and physical activity will be adjusted for in the analysis. To assess the generalizability of the adverse effect of POP exposure across various subgroups of postmenopausal women, we will evaluate POPs’ associations with atherosclerosis progression in subgroups of women randomized to HT and placebo, as well as early and late postmenopausal groups. This study will provide important evidence on long- term effect of POP mixtures on atherosclerosis progression and related metabolic and inflammatory pathophysiology among postmenopausal women who are at high risk of CVD. Findings from this study will help identify key individual and subgroups of POPs as targets for regulations, remediations, and CVD prevention.

抽象的 心血管疾病（CVD）是美国和全球女性死亡的主要原因。更年期 转变导致心血管疾病的风险显着升高，使绝经后妇女成为特殊人群 注意力。人们越来越担心接触环境化学物质，特别是持久性化学物质 有机污染物（POP）会扰乱人类内分泌环境并对心血管健康产生不利影响。这 持久性有机污染物在一生中的生物累积会对健康产生重大的长期影响，尤其是对老年人 人口。然而，POPs 对亚临床动脉粥样硬化进展的长期影响是早期 CVD的病理特征在绝经后妇女中尚未得到很好的研究。此外，POPs的影响 尚未在美国人群中评估其对动脉粥样硬化进展的影响。据我们所知，没有纵向 已经进行了研究来调查 POP 混合物和动脉粥样硬化进展的影响。唯一的 纵向研究报告特定类别的持久性有机污染物、全氟烷基物质和多氟烷基物质的不利影响 （PFAS），关于 10 年来颈动脉内膜中层厚度（IMT、超声）增加的研究来自瑞典 高级队列。为了填补我们理解上的空白，我们将研究血浆的长期关联 独特队列中绝经后妇女的持久性有机污染物浓度和动脉粥样硬化进展；早期 vs 雌二醇后期干预试验 (ELITE)，对亚临床颈动脉进行 5 年纵向测量 动脉粥样硬化，包括金标准超声测量（IMT、回声性和硬度）和冷冻 血浆样本用于分析 4 个主要类别（多氯 联苯 (PCB)、多溴二苯醚 (PBDE)、有机氯化农药 (OCP) 和 （PFAS）。 ELITE 是一项随机临床试验，包括 596 项早期（绝经后 <6 年）和晚期（≥10 年） 自绝经后）绝经后妇女比较 5 年内动脉粥样硬化进展率 随机接受激素治疗（HT）和安慰剂的女性之间的研究。超出了调查效果的目标 POP混合物对动脉粥样硬化进展的影响，我们将研究POP混合物对危险因素的影响 动脉粥样硬化，包括代谢（脂质、葡萄糖、HbA1c 和胰岛素抵抗）和炎症 生物标志物。重要的协变量包括设计因素（HT 和安慰剂、绝经后早期和晚期 组）、肥胖、吸烟、饮食和体力活动将在分析中进行调整。评估 POP 暴露不利影响对绝经后妇女各个亚组的普遍性，我们 将评估随机接受 HT 和 HT 治疗的女性亚组中 POP 与动脉粥样硬化进展的关联 安慰剂以及早期和晚期绝经后组。这项研究将为长期研究提供重要证据 POP 混合物对动脉粥样硬化进展及相关代谢和炎症的长期影响 CVD 高风险绝经后妇女的病理生理学。这项研究的结果将有助于 确定持久性有机污染物的关键个体和亚群作为监管、补救和心血管疾病预防的目标。