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

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.