Neurodevelopmental disorders (NDDs) affect 1 in 10 children in the US and rates are increasing at an alarming rate. Gene-environment interactions are implicated in the pathogenesis of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). Epigenetic changes, such as DNA methylation, are often posited 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 to address this gap in the literature by testing the hypothesis that PCB 95 interacts with heritable mutations in Ca2+ signaling at the level of DNA methylation to modulate Wnt2-dependent dendritic growth and plasticity. To test this hypothesis, I will model a gene-environment interaction relevant to ASD by combining exposure to polychlorinated biphenyl (PCB) 95, an environmental neurotoxicant, and mice with a CGG repeat expansions in the premutation range (<200 repeats) in the fragile X mental retardation gene (Fmr1), which is the single most frequent monogenetic cause of neurodevelopmental impairments, or a novel double knock in (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 dendritic arborization 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 CGG repeat 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 and Wnt2 DNA methylation and these effects are amplified in Fmr1 premutation and KI mouse neurons. (2) Test the hypothesis that DNA methylation serves as a convergence point for PCB 95, and heritable mutations in Ca2+ signaling, combined effects on dendritic growth and plasticity in vivo. This project will yield novel mechanistic data regarding not only the developmental neurotoxicity of PCBs, which are a current risk to the developing 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 is urgently needed to inform rational strategies for minimizing NDD risk by mitigating relevant exposures in susceptible populations and for identifying novel therapeutic targets. This research experience combined with the training plan developed in consultation with my Sponsor and Co-Sponsor will enhance and extend my predoctoral training and provide me with not only the research tools but also the professional skills required to transition to independence and realize my career goal of becoming an independent investigator in environmental epigenetics.
Autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) are a growing concern with diagnosis in more than 1 in 10 children born in the United States each year. Alarmingly, incidence of ASD is increasing - a trend which cannot completely be explained by increased awareness and broader diagnostic criteria. Environmental factors are implicated in the pathogenesis of these disorders and postulated to interact with genetic susceptibilities. However, the mechanisms by which environmental chemicals interact with genetic factors to confer individual risk remain a current knowledge gap in our understanding of ASD etiology. DNA methylation is a critical gene expression regulatory mechanism in normal brain development and ASD, which can be influenced by environmental chemicals as well as dietary supplementation with folic acid. Thus, DNA methylation may act at the interface of genetic and environmental ASD risk and protective factors. These studies will combine environmental exposure in genetically susceptible mouse models to identify DNA methylation as a convergent target of gene and environment exposures, and provide a rational approach for effective intervention strategies to reduce the incidence or severity of neurodevelopmental disorders.
