Nearly one-in-five children in the U.S. continue to be exposed to environmental tobacco smoke (ETS) in the home. Epidemiological data suggest that childhood ETS exposure increases risk for behavioral and cognitive problems and related neurobehavioral disorders independent of prenatal exposure. Yet, it remains unknown whether post-term ETS exposure has a direct neurobiological effect on the highly-plastic young brain to cause reported neurological deficits and psychiatric disorders. Such knowledge is fundamental to support long-term mechanistic research, with potential to influence individual decisions and policy, and to develop novel predictive diagnostics that are of benefit to human health. Thus, here we propose exploratory research, promoted by the present award mechanism, using a newly developed animal model of postnatal ETS exposure demonstrated to induce relevant behavioral deficits in attention, activity and impulse control. Preliminary findings show that ETS induces significant perturbation to mitochondrial energetics signifying an abnormal transient hypermetabolic state during critical period development in the juvenile cerebellum, followed by hypometabolism indicative of depressed function with maturation in adolescence. The cerebellum provides correction and flexibility in cortical-mediated functions; thus, our preliminar findings provide rationale for the innovative hypothesis that post-term ETS-induced perturbed energetics underlies developmental susceptibility and dysfunction within key cortical circuitry mediating higher-order behavioral deficits in animals. We will test our central hypothesis with a modern systems-based approach across two Specific Aims:
Aim 1 will test an effect of post-term ETS exposure on mitochondrial energetics within developing higher-order circuitry and subsequent functional depression in adolescence.
Aim 2 will develop innovative methodology to selectively resolve novel biochemical networks correlated with ETS-induced mitochondrial perturbation in higher-order circuitry. Expected findings will provide anatomical and biochemical mechanistic insight into ETS- induced energetic perturbation during critical period higher-order circuit development and subsequent adolescent dysfunction. These results would provide a breakthrough link between ETS-induced aberrant behavior by showing dysfunction in responsible circuitry, advancing our current understanding on biological causation of neurodevelopmental deficits and disorders. We further anticipate that results from these studies will support future research intent on translating these findings into prognostic biomarkers of susceptibility to ETS for targeted intervention of at-risk children in the U.S. and abroad.
Nearly one-in-five children in the U.S. are still exposed to environmental tobacco smoke (ETS) in the home with recently epidemiology suggesting that they are at greater risk for behavioral and cognitive problems. We propose the new concept that postnatal ETS exposure has a direct effect on neurodevelopment altering crucial mechanisms of mitochondrial proliferation during ongoing circuit formation. Results will further knowledge of the mechanisms by which childhood ETS exposure impacts the developing brain and support the development of diagnostics and therapeutics targeting mitochondrial mechanisms.
| Aragon, Mario J; Topper, Lauren; Tyler, Christina R et al. (2017) Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood-brain barrier impairment. Proc Natl Acad Sci U S A 114:E1968-E1976 |
