Project 2: Mechanisms of Neurobehavioral Dysfunction from Developmental Nicotine & Tobacco

 

Project Leader: Ed Levin, PhD

  • Co-Investigator: Theodore Slotkin, PhD

  • Co-Investigator: Lisa Satterwhite, PhD

  • Co-Investigator: Fred Seidler, PhD

 

This research project will determine how early life secondhand smoke exposure impacts neuronal differentiation, neural circuit formation and behavioral development resulting in persisting cognitive and emotional dysfunction.

What are we going to test? Neuronal and behavioral mechanisms will be studied in experiments tracing the progress from the incipient exposures to nicotine and tobacco during critical stages of cellular and organismal development, to the epigenetic and synaptic mechanisms that underlie behavioral dysfunction. Impacts on attention and memory as well as emotional function will be determined in the rat model so that the cause-and-effect relationship can be determined.

How are we going to do this? We will compare the effects of tobacco and nicotine ranging from higher exposures modeling active maternal smoking to lower exposures characteristic of secondhand smoke. Using a well characterized rat model for neurodevelopment, tobacco smoke extract and nicotine will be administered by minipumps implanted subcutaneously to enable for continuous exposure that avoids the known stressors for rats that accompany direct smoke exposure.

Human in vitro models of embryonic stem cells and neural progenitor cells will be used to identify concordance between cells exposed to nicotine and tobacco smoke extract in vitro and in vivo from children and mothers exposed to active smoking or second-hand smoke during pregnancy in Project 1. Sex-specific epigenetic and genomic signatures will be modeled using male and female embryonic stem cells. Simple micronutrients will be tested for the ability to reverse smoking-associated epigenetic change and altered synaptic phenotypes in 3-D mini-brains assembled from human neural progenitors.

This project will provide the mechanistic link translating the epigenetic impacts of secondhand smoke to the cognitive impairments seen in children after developmental secondhand smoke exposure. Synaptic mechanisms underlying these behavioral effects will be determined with assessment of acetylcholine, dopamine, norepinephrine and serotonin systems known to be affected by nicotine exposures associated with active smoking during pregnancy. Cellular phenotypes of secondhand smoke and nicotine exposure will be determined in two validated in vitro models of neurodifferentiation, nerve growth factor-induced differentiation of rat PC12 cells and differentiation of rat embryonic stem cells (rESCs) to neurons and glia.

How will the findings help us improve children's health? The investigation of epigenetic and neurochemical alterations from secondhand smoke will lead to studies of rescue and therapeutic treatments to avoid or reverse developmental secondhand smoke-induced cognitive and emotional dysfunction. This project will provide critical mechanistic translation between the molecular epigenetic studies of Project 3 and the clinical studies of ADHD in Project 1 to help children avoid lifelong impairment from developmental secondhand smoke exposure.

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