Prenatal metal-stress mixtures and transdiagnostic pathways to preadolescent internalizing disorders: Role of placental molecular signaling

产前金属应激混合物和青春期前内化障碍的跨诊断途径：胎盘分子信号传导的作用

• 批准号: 10303949
• 负责人: Rosalind J Wright
• 金额: $ 60.81万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10303949
• 关键词: Address; Adolescence; Affect; Age; Anxiety; Anxiety Disorders; Arousal; Arsenic; Attention deficit hyperactivity disorder; Autonomic nervous system; Behavior; Behavioral; Biogenesis; Biological Assay; Biological Markers; Biological Testing; Birth; Blood; Brain; Brain region; Cadmium; Chemicals; Childhood; Chronic; Clinical; Cognition; Complex; Complex Mixtures; Conduct Disorder; Data; Depressive disorder; Development; Dimensions; Disease; Emotional disorder; Environmental Risk Factor; Etiology; Event; Exposure to; General Population; Health; Individual; Intelligence; Intervention; Joints; Lead; Learning; Life; Link; Longitudinal Studies; Manganese; Measures; Mediation; Mediator of activation protein; Mental Depression; Mental Health; Mercury; Metal exposure; Metals; MicroRNAs; Molecular; Mood Disorders; Morbidity - disease rate; Motion; National Institute of Environmental Health Sciences; Negative Valence; Neuraxis; Neurosecretory Systems; Outcome; Oxidative Stress; Pathway interactions; Performance; Physiological; Placenta; Plant Roots; Plasma; Policies; Pregnancy; Prevention; Process; Psychopathology; Psychosocial Factor; Psychosocial Stress; Public Health; Regulation; Research; Research Domain Criteria; Risk; Risk Assessment; Risk Factors; Role; Shapes; Signal Transduction; Stress; Symptoms; Synaptic Transmission; System; Time; Tissues; Umbilical Cord Blood; Work; Youth; Zinc; attentional control; behavior measurement; biological adaptation to stress; cognitive control; cognitive process; cognitive system; cohort; comorbidity; depressive symptoms; early detection biomarkers; early life adversity; environmental chemical; externalizing behavior; fetal; follow-up; hypothalamic-pituitary-adrenal axis; in utero; infancy; lens; metal poisoning; nervous system development; neurotoxicity; post-traumatic symptoms; preadolescence; prenatal; prenatal exposure; prenatal stress; programs; psychologic; relating to nervous system; social stressor; stressor; symptomatology; theories; trait

Internalizing problems, most prominently anxiety and depressive disorders, affect 400 million people globally. Rooted in childhood, there is a sharp rise in these disorders during the transition to adolescence. Environmental influences on mental health risk begin in utero. The fetal brain is particularly plastic, thus prenatal exposures may have greater effects on lifetime mental health compared to later exposures. Metals remain a public health concern as even low-level exposures typical in the US can disrupt CNS development, especially during the fetal period. Longitudinal studies on the role of prenatal metal exposures in emerging mood and anxiety disorders are sparse. Moreover, studies on metal neurotoxicity largely consider one chemical at a time. The National Institutes of Environmental Health Sciences (NIEHS) has prioritized the need to examine health effects of chemical mixtures, as well as the joint effects of chemical and social stressors, to better reflect real-life exposure scenarios and inform more refined policies to protect the public. Learning and intellectual performance are complex processes that integrate with behavioral traits and cognitive processes over development to shape psychological health. Metal toxicity disrupts brain regions and functional connectivity implicated across a number of transdiagnostic (TD) features of disordered emotional states. Metals and psychosocial stress disrupt similar but not completely overlapping processes that may be involved, thus they can interact in complex ways. We leverage an ongoing pregnancy cohort with extensive prenatal metal and stress exposure data, placental molecular signaling biomarkers, and transdiagnostic measures across infancy and childhood with follow-up to age 9-11 years proposed herein, to more comprehensively elucidate the role of in utero metals and stress exposures in the programming of internalizing problems emerging in preadolescence. We will consider transdiagnostic (TD) dimensional factors across select Research Domain Criteria (RDoC) including (1) negative valence systems, (2) cognitive systems, and (3) arousal/regulation. We use placental-derived microRNA data and physiological stress responsivity (hypothalamic-pituitary-adrenal axis, autonomic nervous system) in infancy to test for biological mechanistic pathways that underlie links between prenatal metals and psychiatric vulnerability across childhood and adolescence. The focus on dimensional assessments of risk factors, mediators, and psychopathological outcomes broadens the applicability of the findings, particularly given the recognized comorbidity at the clinical level and the high rate of anxiety and depressive problems at the subclinical level in the general population as well as in youth specifically. Explicating modifiable environmental risk factors and early biomarkers of risk so that interventions can be applied early to promote optimal development may have significant implications for prevention of chronic psychopathology.

内在化问题，最突出的是焦虑和抑郁障碍，影响着全球4亿人。 根植于童年，在过渡到青春期期间，这些障碍急剧上升。 环境对精神健康风险的影响始于子宫。胎儿的大脑特别具有可塑性，因此 与后来的暴露相比，产前暴露对终生心理健康的影响可能更大。金属 仍然是一个公共卫生问题，因为即使是在美国常见的低水平暴露也会扰乱中枢神经系统的发育。 尤其是在胎儿时期。产前金属暴露在新发疾病中作用的纵向研究 情绪障碍和焦虑症很少见。此外，对金属神经毒性的研究主要考虑一种 一次使用化学药品。美国国家环境健康科学研究院(NIEHS)已将这一需求列为优先事项 检查化学混合物对健康的影响，以及化学和社会应激源的联合影响，以 更好地反映现实生活中的暴露场景，并为保护公众的更精细政策提供信息。学习和 智力表现是与行为特征和认知过程相结合的复杂过程 过度发展塑造心理健康。金属中毒扰乱脑区和功能 情绪障碍状态的多种跨诊断(TD)特征与连接性有关。 金属和心理社会压力扰乱了可能涉及的类似但不完全重叠的过程， 因此，它们可以以复杂的方式相互作用。我们利用持续的怀孕队列进行广泛的产前检查 金属和压力暴露数据、胎盘分子信号生物标记物和跨诊断措施 跨越婴儿期和儿童期，并在此建议对9-11岁进行随访，以更全面地 阐明子宫内金属和压力暴露在内化问题中的作用 出现在青春期前。我们将考虑跨选择的跨诊断(TD)维度因素 研究领域标准(RDoC)包括(1)负价系统，(2)认知系统，和(3) 觉醒/调节。我们使用胎盘来源的microRNA数据和生理应激反应 (下丘脑-垂体-肾上腺轴，自主神经系统)在婴儿期测试生物机制 产前金属与儿童和儿童精神疾病易感性之间联系的途径 青春期。重点放在风险因素、介体和精神病理学的维度评估上 结果扩大了研究结果的适用性，特别是考虑到临床上公认的合并症。 亚临床水平的焦虑和抑郁问题在一般人群中的水平和高比率 尤其是在青年时期。阐明可改变的环境风险因素和风险的早期生物标记物 可以及早应用干预措施来促进最佳发展可能对 慢性精神病的预防。