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

内在问题，尤其是焦虑症和抑郁症，影响着全球 4 亿人。 这些疾病根源于童年，在向青春期过渡期间急剧增加。 环境对心理健康风险的影响从子宫内就开始了。胎儿大脑的可塑性特别强，因此 与以后的暴露相比，产前的暴露可能对一生的心理健康产生更大的影响。金属 仍然是一个公共卫生问题，因为即使是美国常见的低水平接触也会扰乱中枢神经系统的发育， 尤其是在胎儿时期。产前金属暴露对新兴婴儿的影响的纵向研究 情绪和焦虑障碍很少见。此外，关于金属神经毒性的研究主要考虑之一 一次化学。美国国立环境健康科学研究所 (NIEHS) 优先考虑了这一需求 检查化学混合物对健康的影响，以及化学和社会压力源的联合影响， 更好地反映现实生活中的暴露场景，并为保护公众提供更完善的政策。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。金属毒性会破坏大脑区域和功能 连通性涉及紊乱情绪状态的许多跨诊断（TD）特征。 金属和社会心理压力会破坏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互动。我们利用持续妊娠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志物和跨诊断措施 涵盖婴儿期和儿童期，并跟踪至本文提出的 9-11 岁，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) 唤醒/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 产前金属与儿童期和精神脆弱性之间联系的途径 青春期。重点关注风险因素、中介因素和精神病理学的维度评估 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 总体人群中亚临床水平的焦虑和抑郁问题的高发生率 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志物，以便 尽早采取干预措施以促进最佳发展可能会对以下方面产生重大影响： 预防慢性精神病理学。

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.