Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by core features of impulsivity, hyperactivity, and attention deficits, which is estimated to affect 8-12% of school-aged children worldwide. While ADHD is a complex disorder with significant genetic contributions, no single gene has been linked to a significant percentage of cases, suggesting that environmental factors or gene-environment interactions may contribute to the etiology of ADHD. Several environmental factors have been identified as potential risk factors for ADHD, including prenatal exposure to alcohol, tobacco, and lead. However, studies of environmental risk factors for ADHD have been hindered by the difficulties of quantifying environmental exposures in humans along with the impossibility of conducting experimental exposures of humans due to ethical considerations. To advance progress in this area, the goal of the current application is to develop a """"""""Virtual Consortium"""""""" between experts in neurotoxicology (Dr. Richardson), ADHD genetics (Dr. Faraone), and environmental epidemiology and children's health (Drs. Yolton, Lanphear and Froehlich) to promote translational research exploring the relationship between developmental pyrethroid exposure and ADHD. This application builds on Dr. Richardson's current grant entitled """"""""Mechanisms of Pesticide-Induced Neurobehavioral Deficits: Relevance to ADHD"""""""". Data generated from this grant has demonstrated that developmental exposure of mice to the pyrethroid pesticide deltamethrin produces neurochemical and behavioral dysfunction similar to that observed in ADHD patients. Furthermore, epidemiological data reveal that elevated urinary pyrethroid metabolite levels in children increases risk of ADHD diagnosis in children 2-3 fold. This proposal seeks to identify alterations in gene expression in an animal model of ADHD based on developmental pesticide exposure, validate these molecular biomarkers in samples from a well characterized cohort of ADHD patients, and to test the association between pesticide exposure, gene expression changes, and behavioral alterations in an ongoing prospective birth cohort.
Richardson, Jason R Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by core features of impulsivity, hyperactivity, and attention deficits and is estimated to affect 8-12% of school-aged children worldwide. Although ADHD is a complex disorder with significant genetic contributions, no single gene has been linked to a significant percentage of cases, suggesting that environmental factors or gene- environment interactions may contribute to the etiology or clinical manifestation of ADHD. The identification of gene expression alterations in animal models of ADHD and lymphoblast cell lines of ADHD patients, and the linkage of these alterations to specific behaviors of children with documented exposure to pyrethroid pesticides would aid greatly in understanding the molecular mechanisms responsible for neuronal dysfunction in ADHD and in the identification of biomarkers of behavioral alterations. Furthermore, this research proposal is significant because it will test the linkage between low-level exposures to pyrethroid pesticides with executive functions and ADHD-related behaviors in children for whom exposure data from the in utero and postnatal period is available. These data will fill an important data gap and are essential for risk assessment of developmental exposures to pesticides. Furthermore, these data would aid in the prevention of ADHD, which is one of the most prevalent neurobehavioral disorders of childhood, with implications for improving successful functioning throughout life. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
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