Investigation of epitranscriptomic crosstalks related to autism using real patients and brain organoids

About This Grant

Project Summary Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition affecting 1 in 36 U.S. children annually. While genetic, epigenetic, and environmental factors contribute to ASD, the mechanisms by which environmental exposures disrupt neurodevelopment remain poorly understood. Emerging evidence highlights the role of epitranscriptomic modifications, such as N6-methyladenosine (m6A), in regulating brain development and synaptic plasticity. This study investigates how prenatal environmental exposures (e.g., cadmium, PFAS) and protective factors (e.g., folic acid) disrupt epitranscriptomic crosstalk, contributing to ASD pathogenesis. Using the MARBLES and EARLI cohorts, we will analyze maternal exposure data and biospecimens to identify exposure-specific epitranscriptomic signatures. Brain organoids derived from induced pluripotent stem cells (iPSCs) will model the effects of environmental toxicants and folic acid on neurodevelopment and m6A regulation. Multi-omics approaches, including RNA-Seq, DNA methylation assays, and MeRIP-Seq, will uncover molecular changes linked to ASD. Machine learning algorithms will integrate multi-omics data to develop predictive models for ASD risk and severity. We propose to investigate four aims: Investigate prenatal environmental exposures’ effects on RNA modifications and DNA methylation; Assess sex-specific epitranscriptomic modifications linked to ASD phenotypes; Evaluate exposure impacts on ASD-associated epitranscriptomic changes using brain organoids; Develop predictive models for ASD risk based on disrupted epitranscriptomic crosstalks. This study bridges human epidemiologic data with organoid modeling to explore the etiology of ASD. By focusing on environmental exposures and protective factors, it addresses critical knowledge gaps and provides a foundation for non-invasive screening tools and targeted interventions. The findings will advance understanding of how environmental factors interact with epitranscriptomic regulation to influence neurodevelopment, paving the way for precision medicine strategies to mitigate ASD risk.