CNS Toxicity of Ambient Air Pollution: Postnatal Exposure to Ultrafine Particles

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DESCRIPTION (provided by applicant): Increasing evidence suggests that the inflammation/cytokine activating effects of air pollutants such as ultra fine particles (UFP) on lung may also occur in brain. In fact, based on such mechanisms, UFP might be predicted to produce CNS effects similar to those seen with maternal/neonatal inflammation, components of which are considered models of schizophrenia, autism cerebral palsy, mental retardation and Parkinson's disease. Consistent with this possibility, preliminary data presented here shows that postnatal UFP exposures results in sustained brain inflammation in mice as adults in ventral midbrain and hippocampus, brain regions key to mediating complex cognition and motor functions. Such residual inflammation suggests that developmental UFP exposure may represent a heretofore largely underappreciated risk factor for neurodevelopment dysfunction in children or a fetal risk factor for neurodegenerative diseases. To evaluate this possibility, experiments proposed here test the hypotheses that: 1) based on sustained damage to hippocampus and ventral midbrain, these same postnatal UFP exposures will produce gender-specific impairments in mice in cognitive and motor functions; and 2) behavioral impairments will be related to alterations in levels of brain cytokines, inflammation, oxidative stress, neurotransmitters and/or plasma corticosterone. Behavioral assessment will include measures of learning, impulsivity and working memory to provide an assessment of comparative sensitivity across these cognitive domains, and will also include the ontogenic profile of locomotor activity across time. Similarly, the longitudinal determination of multiple markers of inflammation, cytokine activation, and oxidative stress and neurotransmitter changes recognizes the potential for multiple mechanisms and will provide initial information on potential mechanistic bases of behavioral changes. Positive findings would establish the basis for a broad expansion of research to include other air pollutant exposures with potential brain impacts (ozone), combined exposures, role of developmental period of exposure, mechanisms by which peripheral UFP activates brain cytokines, etc. Such studies could lead to significant advances in understanding the contribution of air pollutants to the etiology of neurodevelopment and neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: Increasing evidence suggests that ultrafine particle (UFP) air pollution may produce sustained brain inflammation. The proposed feasibility studies will test whether developmental UFP exposures of mice can affect cognitive and/or locomotor behavior, and mechanisms by which they are disrupted. Positive findings would suggest that UFP represents a previously underappreciated basis for brain dysfunction.