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: 10631120
• 负责人: Rosalind J Wright
• 金额: $ 58.18万
• 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/10631120
• 关键词: Adolescence; Affect; Age; Anxiety; Anxiety Disorders; Arousal; Arsenic; Attention; Attention deficit hyperactivity disorder; Autonomic nervous system; Behavior; Behavioral; Biogenesis; Biological Assay; Biological Markers; Biological Testing; Birth; Blood; Brain; Brain region; Cadmium; Central Nervous System; Chemicals; Childhood; Chronic; Clinical; Cognition; Complex; Complex Mixtures; Conduct Disorder; Data; Depressive disorder; Development; Diagnostic; Dimensions; Disease; Emotional disorder; Environment; Environmental Risk Factor; Event; Exposure to; General Population; Health; Individual; Intelligence; Intervention; Joints; Lead; Learning; Life; Link; Longitudinal Studies; Manganese; Measures; Mediation; Mediator; Mental Depression; Mental Health; Mercury; Metal exposure; Metals; MicroRNAs; Molecular; Mood Disorders; Morbidity - disease rate; Motion; National Institute of Environmental Health Sciences; Negative Valence; Neurosecretory Systems; Outcome; Oxidative Stress; Pathway interactions; Performance; Persons; Physiological; Placenta; 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; 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; neural; neurotoxicity; post-traumatic symptoms; preadolescence; prenatal; prenatal exposure; prenatal stress; programs; psychologic; 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.

内部化问题，最突出的焦虑和抑郁症，全球影响4亿人。 植根于童年时代，在过渡到青春期期间，这些疾病急剧上升。 环境对心理健康风险的影响始于子宫。胎儿大脑特别塑料，因此 与以后的暴露相比，产前暴露对终生心理健康的影响可能更大。金属 仍然是公共健康问题，即使在美国典型的低级暴露也可能破坏CNS的发展， 特别是在胎儿时期。关于产前金属暴露在出现的作用的纵向研究 情绪和焦虑症很少。此外，关于金属神经毒性的研究在很大程度上考虑了一个 一次化学。国家环境健康科学研究所（NIEHS）优先考虑需求 检查化学混合物的健康影响以及化学和社会压力的关节作用， 更好地反映现实生活中的暴露场景，并告知更多精致的政策以保护公众。学习和 智力绩效是与行为特征和认知过程相结合的复杂过程 塑造心理健康的发展。金属毒性破坏了大脑区域和功能 情绪状态无序的许多经诊断（TD）特征涉及的连通性。 金属和社会心理压力破坏了可能涉及的类似但不完全重叠的过程， 因此，他们可以以复杂的方式进行互动。我们利用正在进行的怀孕队列和广泛的产前 金属和压力暴露数据，胎盘分子信号生物标志物和转诊措施 在婴儿期和童年期，此处提出的随访，以至于更全面地 阐明子宫金属中的作用和压力暴露在内部化问题的编程中 在前青年中出现。我们将考虑选择的转诊（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） 唤醒/调节。我们使用胎盘衍生的microRNA数据和生理压力响应性 （下丘脑 - 垂体 - 肾上腺轴，自主神经系统）在婴儿期测试生物机械机制 童年和整个儿童和精神病脆弱性之间联系的途径是童年和精神病脆弱性 青春期。关注危险因素，调解人和心理病理学的维度评估 结果扩大了调查结果的适用性，特别是考虑到临床上公认的合并症 一般人群中亚临床水平上的焦虑和抑郁问题的高度和高度的速度 以及在青年时期。阐明可修改的环境风险因素和危险的早期生物标志物，因此 可以尽早采用干预措施来促进最佳发展，可能对 预防慢性心理病理学。