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

内化问题，最突出的是焦虑和抑郁症，影响着全球4亿人。 这些疾病起源于童年，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开始于子宫内。胎儿的大脑特别可塑，因此， 与以后的接触相比，产前接触可能对终生心理健康产生更大的影响。金属 仍然是一个公共卫生问题，因为即使是美国典型的低水平暴露也会破坏CNS发育， 尤其是在胎儿期。产前金属暴露在新生儿中作用的纵向研究 情绪和焦虑障碍很少。此外，对金属神经毒性的研究主要考虑一个 化学品一次美国国立环境健康科学研究院（NIEHS）已将这一需求列为优先事项。 研究化学混合物对健康的影响，以及化学和社会压力的联合影响， 更好地反映现实生活中的暴露情景，并为更完善的政策提供信息，以保护公众。学习和 智力表现是一个复杂的过程，它与行为特征和认知过程相结合 以塑造心理健康。金属中毒破坏大脑区域和功能 连接性涉及紊乱情绪状态的许多跨诊断（TD）特征。 金属和心理社会压力破坏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。我们利用一个正在进行的妊娠队列， 金属和应激暴露数据、胎盘分子信号传导生物标志物和转诊断措施 在婴儿期和儿童期，随访至9-11岁，更全面地 阐明子宫内金属和压力暴露在内化问题编程中的作用 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），以测试生物机制 产前金属和儿童期精神脆弱性之间联系的基础途径， 青春期关注危险因素、介质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， 水平和高比例的焦虑和抑郁问题在亚临床水平的一般人口， 尤其是在年轻人中。阐明可改变的环境风险因素和风险的早期生物标志物， 可以及早采取干预措施以促进最佳发展，这可能对以下方面产生重大影响： 预防慢性精神病

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.