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

This animal study found that mothers who were obese before getting pregnant had male offspring with autism-like behaviors, even when the mothers weren't obese during pregnancy. The researchers found changes in brain genes and chemical markers that affect how brain cells connect. Female offspring weren't affected. This suggests that a mother's health before conception may influence autism risk in her children.

This mouse study examined how maternal obesity before conception affects autism-like behaviors in offspring. Using IVF and embryo transfer, researchers separated pre-conception from gestational obesity effects. Male offspring from mothers on high-fat diets before conception showed autism-like behaviors including altered vocalizations, reduced sociability, and repetitive grooming, while female offspring were unaffected. Brain analysis revealed dysregulation of autism-related genes and epigenetic changes, specifically hypomethylation of gene promoters leading to altered protein expression that disrupts brain cell connections.

The findings suggest maternal health before pregnancy is a critical, modifiable risk factor for autism spectrum disorder.

Findings suggest pre-conception maternal health optimization could be a preventive strategy for ASD risk reduction. Results support the importance of nutritional counseling and weight management for women planning pregnancy, particularly given the sex-specific effects observed in male offspring.

Animal model findings may not directly translate to humans. Sample size not reported. Only examined short-term behavioral outcomes. Limited to specific mouse strain and diet composition. Epigenetic analysis restricted to hippocampal tissue.

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, includingand. Whole-genome bisulfite sequencing of hippocampal tissue showed hypomethylation of an alternativepromoter, correlating with increased expression of the short isoform, 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.