Convergent neural correlates of prenatal exposure to air pollution and behavioral phenotypes of risk for internalizing and externalizing problems: Potential biological and cognitive pathways

Abstract

Humans are ubiquitously exposed to neurotoxicants in air pollution, causing increased risk for psychiatric outcomes. Effects of prenatal exposure to air pollution on early emerging behavioral phenotypes that increase risk of psychopathology remain understudied. We review animal models that represent analogues of human behavioral phenotypes that are risk markers for internalizing and externalizing problems (behavioral inhibition, behavioral exuberance, irritability), and identify commonalities among the neural mechanisms underlying these behavioral phenotypes and the neural targets of three types of air pollutants (polycyclic aromatic hydrocarbons, traffic-related air pollutants, fine particulate matter < 2.5 µm). We conclude that prenatal exposure to air pollutants increases risk for behavioral inhibition and irritability through distinct mechanisms, including altered dopaminergic signaling and hippocampal morphology, neuroinflammation, and decreased brain-derived neurotrophic factor expression. Future studies should investigate these effects in human longitudinal studies incorporating complex exposure measurement methods, neuroimaging, and behavioral characterization of temperament phenotypes and neurocognitive processing to facilitate efforts aimed at improving long-lasting developmental benefits for children, particularly those living in areas with high levels of exposure.

Keywords: Air pollution; Animal models; Behavioral phenotypes; Neural mechanisms.

Figure 1.. Convergence of evidence from animal models of prenatal exposure to air pollution and altered behavioral phenotypes with developmental models of human psychiatric risk.

The gradient bar illustrates how the studies reviewed herein cover animal models (red) and human studies (blue) and where these overlap conceptually (cross-species phenotypes; shown in purple). Light blue arrows from “exposure” to “neural correlates” and dark blue lines from “exposure” to analogous – back-translated – ”animal phenotypes” show potential mechanisms of exposure on human psychiatric risk. Solid versus dashed lines indicate more versus less persuasive evidence (Table 2). Observational studies linking human prenatal exposure to air pollution and alterations in brain structure are described in the text (see Discussion). Animal phenotypes akin to behavioral inhibition (BI) and behavioral exuberance (BE) were assessed in animal models of anxiety (elevated plus maze test, open field test, etc. see Table 1), whereas those akin to irritability were assessed using frustrative non-reward tasks (Table 1). Arrows from “exposure” to “neural correlates” to “animal phenotypes” and from “human phenotypes” to “human psychiatric risk” represent the hypothesized causal model positing that exposure increases psychiatric risk via effects on the brain and behavioral reactivity. ADHD = Attention Deficit hyperactivity Disorder; ODD=Oppositional Defiant Disorder.