Abstract: Autism spectrum disorder (ASD) is a heterogenous, early-onset neurodevelopmental disorder with multifactorial aetiology. There are hundreds of genes that contribute to ASD. Additionally, several environmental factors, such as neurotoxic compounds, endocrine modulators, and neuropsychiatric medications, have been associated with ASD outcomes. We investigated a highly efficient and multiplexable, fractional factorial experimental design to study multiple environmental factors and human induced pluripotent stem cell (iPSC) lines in the context of ASD. RNA expression analysis revealed significant upregulation of pathways related to synaptic function and lipid metabolism, following exposure to lead and fluoxetine, respectively. We validated our findings using mass spectrometry-based metabolomics after fluoxetine exposure. The study demonstrates that the fractional factorial experiment design can be used for multiplexed transcriptomic analyses to detect relevant changes at the pathway level. Our study provides a roadmap for understanding the impact of low-grade environmental exposures on human neurodevelopment. Expansive future studies will require multiple cell lines with different genetic backgrounds for characterising environmental exposures in ASD and other neurodevelopmental disorders.

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bioRxiv; Download PDF; Google Scholar