Understanding the Relationship Between Environmental Endocrine Disrupting Chemicals, Neuropsychiatric Outcomes, and Related Biological Processes in Depression

了解环境内分泌干扰化学物质、神经精神结果和抑郁症相关生物过程之间的关系

• 批准号: 10739590
• 负责人: Jessica A Harder
• 金额: $ 24.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739590
• 关键词: Address; Adverse effects; Affect; Age; Animal Model; Awareness; Behavior; Biological; Biological Markers; Biological Process; Biometry; Brain; Brain-Derived Neurotrophic Factor; C-reactive protein; Chemical Exposure; Chemicals; Child; Childhood; Clinical; Cognition; Cognition Disorders; Cognitive; Collaborations; Competence; Data; Data Collection; Development Plans; Dimensions; Disease; Educational workshop; Elderly; Emotional; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Impact; Environmental Pollutants; Estradiol; Estrogens; Exposure to; Female; Food Packaging; Foundations; Genes; Goals; Gonadal Steroid Hormones; Grant; Growth Factor; Health; Hormonal; Hormones; Impaired cognition; Individual; Inflammation; Inflammatory; Interleukin-6; Intervention; Knowledge; Life; Life Style; Literature; Major Depressive Disorder; Measures; Mediating; Mediation; Mediator; Menopause; Mental Depression; Mentorship; Methods; Methylation; Mood Disorders; Moods; Outcome; Outcome Measure; Pathway interactions; Patients; Pharmaceutical Preparations; Plastics; Postmenopause; Predisposition; Public Health; Public Policy; Qualifying; Recording of previous events; Research; Research Personnel; Risk; Role; Series; Serum; Severities; Standardization; Statistical Methods; Symptoms; Synaptic plasticity; TNF gene; Testing; Testosterone; Therapeutic Intervention; Training; Urine; Vulnerable Populations; Woman; Work; affective disturbance; career development; chemical association; cognitive function; cognitive performance; cognitive testing; cohort; consumer product; cytokine; depressive symptoms; disorder risk; early life exposure; experience; human old age (65+); inflammatory marker; interest; laboratory experience; lifestyle intervention; middle age; mood symptom; neurobehavioral; neuropsychiatric disorder; neuropsychiatric symptom; neuropsychiatry; neurotrophic factor; neurotropic; novel; older women; phthalates; pre-clinical; prenatal; primary outcome; profiles in patients; programs; recruit; sex; symposium; symptomatology; urinary

Environmental endocrine disrupting chemicals (EDCs) are associated with multiple adverse health effects. Early- life exposures alter neurobehavioral trajectories, with increased risk for depression and poorer cognitive functioning in childhood. However, very few studies have evaluated the effects of EDC exposure in later life despite ongoing exposure. Patients with a history of major depression (MDD) are at increased risk for neuropsychiatric symptoms such as low mood and cognitive dysfunction and this risk is further elevated in women during the menopausal and post-menopausal period. Preclinical and clinical evidence suggests that EDCs affect a number of biological variables implicated in mood and cognitive disorders, including inflammatory biomarkers, brain-derived neurotrophic factor (BDNF), and sex hormones. The proposed study seeks to better understand how EDCs affect mood and cognition in postmenopausal women with and without depression. We propose to evaluate 1) the association between EDCs and neuropsychiatric symptoms (mood and cognition) in postmenopausal women with MDD and without mood disorders (healthy controls; HC), 2) the relationship between EDCs and biological variables including inflammatory cytokines like C-reactive protein, interleukin-6, and tumor necrosis factor-α, BDNF, and sex hormones including estradiol and testosterone, and 3) whether the biological variables of interest mediate any potential association of EDCs with neuropsychiatric outcomes. We will leverage ongoing data collection of an existing study of postmenopausal women including depression rating scale scores and detailed cognitive assessment data, as well as serum cytokine, BDNF, and sex hormone levels. Urinary bisphenols and a suite of 16 phthalate metabolites will be measured in 75 MDD and 75 HC subjects. Urine will be collected at 2 timepoints (at recruitment and 1 month later), then pooled for EDC assessment. Regression and statistical methods for mixtures will be used to assess relationships between individual EDCs and their mixtures with neuropsychiatric outcomes and biomarkers. Mediation analysis will explore the direct and indirect effect of EDCs on outcome measures via the biological variables. Career development plan goals include gaining competency in the interpretation of environmental exposures and inflammatory data and in biostatistics, especially mixture methods of analysis. Training goals will be met by coursework, workshops/seminars, conferences, lab experience, readings, and mentorship. Training experiences will mostly take place at Harvard- affiliated BWH and HSPH. This project will identify emotional and cognitive effects and relevant biological effects of EDCs in a population vulnerable to neuropsychiatric symptoms. Enhanced mechanistic understanding will allow novel interventions targeting contributory biological variables, such as lifestyle changes or medications that reduce inflammation, increase BDNF, and regulate sex hormones to mitigate adverse effects of EDCs. Increased awareness of neuropsychiatric implications of EDC exposures may also guide public policy changes that regulate or reduce their omnipresence in consumer products and the environment.

环境内分泌干扰物（EDCs）与多种不良健康影响有关。早- 生活暴露会改变神经行为轨迹，增加患抑郁症的风险， 在童年时期发挥作用。然而，很少有研究评估EDC暴露对晚年生活的影响 尽管持续暴露。有重度抑郁症（MDD）病史的患者， 神经精神症状，如情绪低落和认知功能障碍，这种风险进一步升高， 绝经期和绝经后妇女。临床前和临床证据表明， 内分泌干扰物影响许多与情绪和认知障碍有关的生物学变量，包括炎症 生物标志物、脑源性神经营养因子（BDNF）和性激素。拟议的研究旨在更好地 了解内分泌干扰物如何影响绝经后抑郁和非抑郁妇女的情绪和认知。我们 建议评估1）内分泌干扰物与神经精神症状（情绪和认知）之间的关联， 患有MDD且无情绪障碍的绝经后妇女（健康对照; HC），2）与MDD的关系 内分泌干扰物和生物变量之间的关系，包括炎症细胞因子，如C-反应蛋白，白细胞介素-6， 和肿瘤坏死因子-α，BDNF，以及性激素，包括雌二醇和睾酮，以及3）是否 感兴趣的生物学变量介导内分泌干扰物与神经精神结果的任何潜在关联。我们 将利用现有绝经后女性研究的持续数据收集，包括抑郁评级 量表评分和详细的认知评估数据，以及血清细胞因子、BDNF和性激素水平。 将在75例MDD和75例HC受试者中测量尿双酚和一组16种邻苯二甲酸酯代谢物。 将在2个时间点（招募时和1个月后）采集尿液，然后合并用于EDC评估。 混合物的回归和统计方法将用于评估单个内分泌干扰物之间的关系 以及它们与神经精神病学结果和生物标志物的混合物。调解分析将探讨直接和 内分泌干扰物通过生物学变量对结果测量的间接影响。职业发展计划目标包括 获得解释环境暴露和炎症数据以及生物统计学的能力， 特别是混合物分析方法。培训目标将通过课程作业、讲习班/研讨会， 会议，实验室经验，阅读和指导。培训主要在哈佛进行- 附属BWH和HSPH。这个项目将确定情绪和认知的影响和相关的生物效应 易受神经精神症状影响的人群中的内分泌干扰物。增强的机械理解将 允许针对促成生物变量的新干预措施，如生活方式改变或药物治疗， 减少炎症，增加BDNF，调节性激素以减轻EDCs的不良影响。增加 意识到EDC暴露的神经精神影响也可能指导公共政策的变化， 或减少它们在消费品和环境中的普遍存在。