Epigenetic and Gene Expression Mechanisms of Developmental Manganese Exposure Neurotoxicity and Efficacy of Chronic Methylphendidate Administration on Gene Expression

The etiology of neurodevelopmental disorders, such as Attention Deficit Hyperactivity Disorder (ADHD), are complex as it is known that both genetic and environmental factors influence the development of attentional dysfunction. One known environmental risk factor for developing attention deficits is having elevated exposure to the toxicant manganese (Mn) during childhood and adolescence, however, the underlying mechanisms that may contribute to the risk of attention deficits remain unresolved. In Chapter 1 of my dissertation I present a review of the current understanding of cellular Mn regulation in mammalian systems, the importance of studying early life development as a period of vulnerability to environmental insults, potential epigenetic and neuroinflammatory mechanisms for how developmental Mn exposure may cause attention deficits, and finally how our developmental Mn exposure rodent model may be used to investigate ADHD etiology to inform therapeutic interventions for treating attention disorders. In my Chapter 2, I propose a novel mechanism of our hypofunctioning catecholaminergic system and associated attention deficit Mn neurotoxicity phenotype, involving lasting epigenomic and gene transcriptomic dysregulation of mTOR and Wnt signaling. Lastly, my Chapter 3 addresses how chronic administration of a low dose of methylphenidate that is associated with ameliorating developmental Mn-induced attentional function in a rat model alters gene expression pathways related to epigenetic regulation, inflammation, cell development (Wnt and mTOR), and hypofunctioning catecholaminergic systems in the prefrontal cortex. The following findings may aid future studies to target therapeutic interventions for children at risk of elevated Mn exposure.