Pre-Conception Maternal Obesity Confers Autism Spectrum Disorder-like Behaviors in Mice Offspring Through Neuroepigenetic Dysregulation

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with early-life origins. Maternal obesity has been associated with increased ASD risk, yet the mechanisms and timing of susceptibility remain unclear. Using a mouse model combining in vitro fertilization (IVF) and embryo transfer, we separated the effects of pre-conception and gestational obesity. We found that maternal high fat diet (HFD) exposure prior to conception alone was sufficient to induce ASD-like behaviors in male offspring-including altered vocalizations, reduced sociability, and increased repetitive grooming-without anxiety-related changes. These phenotypes were absent in female offspring and those exposed only during gestation. Cortical transcriptome analysis revealed dysregulation and isoform shifts in genes implicated in ASD, including <i>Homer1</i> and <i>Zswim6</i>. Whole-genome bisulfite sequencing of hippocampal tissue showed hypomethylation of an alternative <i>Homer1</i> promoter, correlating with increased expression of the short isoform <i>Homer1a</i>, which is known to disrupt synaptic scaffolding. This pattern was specific to mice with ASD-like behaviors. Our findings show that pre-conceptional maternal obesity can lead to lasting, isoform-specific transcriptomic and epigenetic changes in the offspring's brain. These results underscore the importance of maternal health before pregnancy as a critical and modifiable factor in ASD risk.