Adolescent exposure to PCBs as a risk factor for the development of depression

ABSTRACT This proposal addresses an urgent need to understand and analyze the impact of environmental factors on the development of psychiatric diseases, such as depression. Adolescents are particularly vulnerable to both developing depression and health impacts of environmental exposures. Emerging evidence suggests that exposure to polychlorinated biphenyls (PCBs) may influence the risk of depression. PCBs are highly pervasive in the environment and biota due to their widespread use, careless disposal, and resistance to degradation. Moreover, recent data demonstrates widespread human exposure to, not only legacy, but also “contemporary” PCB congeners that are unintentional byproducts of current manufacturing processes. A widespread PCB contamination has been identified in schools, highlighting the importance of evaluating the role of PCB exposure on the development of depression in adolescence. Indeed, there is a critical gap of knowledge on the impact of PCBs on depression. The present application is intended to close this gap using adolescent mouse models. The central hypothesis of this proposal is that PCB exposure in adolescence primes for depression. Mechanistically, we will focus on the gut microbiome- brain axis because of the evidence that gut bacteria influence depression and exposure to PCBs induces both the gut dysbiosis and dysfunction of the blood-brain barrier (BBB). We propose the following sequence of events, which will be studied in mouse models chronically exposed to PCBs: gut dysbiosis and disruption of the gut barrier (Aim 1) → dysfunction of the BBB and neuroinflammation (Aim 2) → development of depressive syndromes (Aims 1 and 2). Our translation objective is to demonstrate that exposure to a human-relevant PCB mixture contributes to, and accelerates, the pathomechanisms of depression via the gut microbiome-brain axis and chronic brain neuroinflammatory responses. The significance of our proposal is in its focus on leading public health problems in the US, namely depression in adolescents. The impact of PCBs on the development of depression is largely unknown, making the proposed studies innovative and likely to generate unique data sets. The discoveries resulting from this proposal are expected to have significant epidemiological, economic, and social implications. Knowledge of the underlying mechanism(s) whereby PCBs prime individuals to depression may provide novel targets for pharmacological intervention. As such, outcomes of this application will close a crucial knowledge gap and provide critically important and therapeutically relevant information on the involvement of environmental toxicants in the development of depression in adolescents. Our long-term goal is to characterize how environmental exposures contribute to the pathomechanisms of depression in adolescents and, ultimately, prevent its development through a precision environmental health intervention.