Neurodevelopmental disorders (NDDs) affect 1 in 10 children born in the United States and the incidence of some NDDs, such as autism spectrum disorder is increasing at an alarming rate. Because many NDD- associated genetic variants are neither necessary nor sufficient to cause NDDs, it is increasingly postulated that environmental factors interact with genetic susceptibilities to determine NDD risk. However, identifying specific environmental risk factors for NDD remains a significant challenge. I propose to use a zebrafish model to test the hypothesis that NDD-associated mutations in the mTOR-signaling pathway interact with environmental chemicals that sensitize the ryanodine receptor (RyR), such as polychlorinated biphenyls (PCBs) to exacerbate adverse neurodevelopmental outcomes. The following aims have been created to test this hypothesis: 1) Demonstrate that developmental exposure to RyR-active PCBs modulates neuronal connectivity in the developing zebrafish in an RyR-dependent manner as determined by quantification of dendritic arborization and synaptic density; 2) Assess the role of mTOR signaling in mediating PCB effects on neurodevelopment in zebrafish; and 3) Model a specific gene-environment interaction relevant to NDDs by developing a zebrafish line with a human NDD-linked mutation in mTOR signaling and determine whether this mutation exacerbates the neurotoxicity of RyR-active PCBs. Successful completion of these aims will provide novel mechanistic insights regarding gene-environment interactions that influence NDD risk and will provide an experimental platform to develop higher throughput assays to screen for additional environmental risk factors that affect early neurodevelopment.
More than 1 in 10 children born in the United States each year will be diagnosed with a neurodevelopmental disorder and the incidence of some disorders, such as autism spectrum disorders has increased significantly over the past several decades. It is widely postulated that genetic susceptibilities interact with environmental factors to determine risk for neurodevelopmental diseases; however, identifying specific environmental factors remains challenging. These studies will employ embryonic zebrafish to model environmentally relevant chemical exposures in a genetically susceptible population. The identification of specific environmental risk factors provides a rational approach for effective intervention strategies for reducing the incidence and/or severity of neurodevelopmental disorders by reducing or preventing exposure to environmental factors during pregnancy and early childhood.
| Frank, Daniel F; Miller, Galen W; Harvey, Danielle J et al. (2018) Bifenthrin causes transcriptomic alterations in mTOR and ryanodine receptor-dependent signaling and delayed hyperactivity in developing zebrafish (Danio rerio). Aquat Toxicol 200:50-61 |
| Keil, Kimberly P; Miller, Galen W; Chen, Hao et al. (2018) PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms. Arch Toxicol 92:3163-3173 |
| Chen, Xiaopeng; Walter, Kyla M; Miller, Galen W et al. (2018) Simultaneous quantification of T4, T3, rT3, 3,5-T2 and 3,3'-T2 in larval zebrafish (Danio rerio) as a model to study exposure to polychlorinated biphenyls. Biomed Chromatogr 32:e4185 |
| Miller, Galen W; Chandrasekaran, Vidya; Yaghoobi, Bianca et al. (2018) Opportunities and challenges for using the zebrafish to study neuronal connectivity as an endpoint of developmental neurotoxicity. Neurotoxicology 67:102-111 |
