Air Pollution and Male-Biased Psychiatric Disorders

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Abstract Our studies in mice show that inhaled exposures during development to concentrated ambient ultrafine particle (UFP) air pollution produces neuropathological and behavioral features common to 3 male-biased disorders, i.e., schizophrenia (SCZ), autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), providing biological plausibility to a growing epidemiological literature linking these disorders to air pollution. In fact, the observed features in mice are intriguingly similar to those of SCZ. Our studies were not specifically designed to test these connections. Therefore, the proposed application seeks to determine the specific contribution of developmental UFP exposures to SCZ and the mechanisms initiating these adverse effects and their sex-dependency. Aim 1 tests the hypothesis that developmental UFP exposures will produce, in a UFP concentration-dependent manner, classic as yet unexamined characteristics of SCZ (alterations in cytokine profiles, reductions in parvalbumin interneurons and synaptic density and altered pre-pulse inhibition). SCZ has been linked to increased serum copper (Cu), and markedly elevated brain Cu levels in mice were found after developmental UFP exposure. Excess brain Cu can also produce neurotoxic features consistent with SCZ. Consequently, Aim 2 tests the hypothesis that elevated Cu contamination in ambient UFP is a specific driver of the observed SCZ features. Brain microglial colonization and activation is higher in male brain during the period of our UFP exposures. Given the critical role of microglial activation and inflammation in SCZ, ASD and ADHD, and the inflammatory and redox properties of AP and of Cu, Aim 3 tests the mechanistic role of microglial activation as the initiating mechanism of neurotoxicity in males by administration of the microglial activation inhibitor, minocycline. During adolescence, female brain exhibits greater microglial number/activation state. Thus, Aim 3 also tests the hypothesis that adolescent UFP exposure will enhance vulnerability of females. Findings from these studies assist in defining mechanisms for neuropsychiatric disorders and the basis of their differential vulnerability by sex and a potential need for additional regulation of air pollution for public health protection.