Neurodevelopmental disorders (NDDs) affect 1 in 10 children in the US and rates are increasing at an alarmingrate. Gene-environment interactions are implicated in the pathogenesis of neurodevelopmental disorders(NDDs), including autism spectrum disorder (ASD). Epigenetic changes, such as DNA methylation, are oftenposited as one mechanism by which genes and environment interact to influence individual NDD risk; however,there is a paucity of experimental data in direct support of this mechanism. The goal of my research is toaddress this gap in the literature by testing the hypothesis that PCB 95 interacts with heritable mutationsin Ca2+ signaling at the level of DNA methylation to modulate Wnt2-dependent dendritic growth andplasticity. To test this hypothesis, I will model a gene-environment interaction relevant to ASD by combiningexposure to polychlorinated biphenyl (PCB) 95, an environmental neurotoxicant, and mice with a CGG repeatexpansions in the premutation range (<200 repeats) in the fragile X mental retardation gene (Fmr1), whichis the single most frequent monogenetic cause of neurodevelopmental impairments, or a novel double knockin (KI) mouse carrying a gain of function mutation in the ryanodine receptor (RyR1T486I) and Fmr1 premutation.The rationale derives from the following published observations: (1) Ca2+ dysregulation and dendriticarborization are characteristics of many NDDs; (2) developmental exposure to PCB 95 increases Ca2+signaling and Wnt2-dependent dendritic arborization; (3) the gain of function mutation in RyR1T486I and CGGrepeat expansions in Fmr1 both enhance intracellular Ca2+ and dendritic arborization. The specific aims are:(1) Test the hypothesis that PCB 95 disrupts dendritic growth in vitro by decreasing nuclear DNMT3B andWnt2 DNA methylation and these effects are amplified in Fmr1 premutation and KI mouse neurons. (2) Testthe hypothesis that DNA methylation serves as a convergence point for PCB 95, and heritable mutations inCa2+ signaling, combined effects on dendritic growth and plasticity in vivo. This project will yield novelmechanistic data regarding not only the developmental neurotoxicity of PCBs, which are a current risk to thedeveloping human brain, but also the role of the epigenome, specifically DNA methylation, in gene-environment interactions that confer risk for adverse neurodevelopmental outcomes. This information isurgently needed to inform rational strategies for minimizing NDD risk by mitigating relevant exposures insusceptible populations and for identifying novel therapeutic targets. This research experience combined withthe training plan developed in consultation with my Sponsor and Co-Sponsor will enhance and extend mypredoctoral training and provide me with not only the research tools but also the professional skills required totransition to independence and realize my career goal of becoming an independent investigator inenvironmental epigenetics.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
