'Pre-conception risk': Maternal obesity triggers autism before pregnancy

Scientists have shown in mice that maternal obesity BEFORE conception can in itself "reprogram" the developing brain of the offspring and cause autism-like behavioral traits in males. The key turned out to be neuroepigenetics: transcriptional networks and DNA methylation in the Homer1 gene, which controls synaptic plasticity, changed at the level of the cortex and hippocampus. The work was published in Cells (MDPI).

Background

• DOHaD context: The idea of “developmental origins of disease” states that the state of parents before and during pregnancy programs the health of the child through metabolic and epigenetic mechanisms. Shifts in DNA methylation, histone modifications, and microRNAs in the placenta and fetal tissues have been shown for obesity.
• Epidemiology: In humans, maternal BMI ≥ 30 before pregnancy is associated with increased odds of NPC/AD in children; meta-analyses and large reviews provide evidence of association but highlight the role of confounding (genetics, social factors) and the need for more rigorous designs.
• Why is the period "before conception" important: maternal obesity affects the oocyte even before fertilization - defects in meiosis, mitochondria and DNA methylation anomalies have been described; some changes do not reverse even after returning to a normal diet. This creates a window of vulnerability precisely before pregnancy.
• How to separate preconception effects from gestational ones: for a “clean” test, IVF + embryo transfer/cross-fostering in animal models is used – this is what is done in the current Cells study, which shows that HFD exposure only before conception in an oocyte donor is already sufficient for the phenotype in the offspring.
• The HOMER1 neuroepigenetic axis: HOMER1/Homer1a are activity-dependent regulators of synaptic plasticity; Homer1a is involved in the housekeeping of excitatory synapses, with implications for learning/memory and network sensitivity. Therefore, the isoform/methylation shifts in Homer1 found in this work appear biologically plausible.
• Sex differences: In humans and animals, autism-related phenotypes are more often expressed in males; recent CDC data confirm a higher prevalence of ASD in boys (male/female ratio ≈3.4:1 in 2022), consistent with male vulnerability in the models.
• The practical public health implication is that the focus on preconception health (weight, insulin resistance, nutrition, inflammation) is justified not only by obstetric but also neurodevelopmental risks; however, experts recommend considering diet/lifestyle changes early and avoiding extreme interventions close to conception.
• Limitations of the data set: Causality is not proven in humans; confounding effects are large. Animal models provide mechanistic clues (oocyte-epigenetics → brain → behavior) but require careful translation to the clinic. The current Cells paper adds a piece to the puzzle: pre-conception maternal exposure can leave a long-lasting neuroepigenetic imprint on offspring.

What did they do?

To separate the effects before conception and during pregnancy, the team used IVF + embryo transfer and cross-fostering. Donor and/or surrogate mothers were fed a high-fat diet (HFD, 45% kcal fat) for 8–10 weeks, creating three groups:

1. CONTROL — donors and surrogates on a normal diet;
2. GAM-HFD - obesity only in oocyte donors (before conception), surrogates are normal;
3. SUR-HFD - normal donors, obesity in surrogate mothers (only during gestation).

The offspring were subjected to a battery of tests: ultrasonic vocalizations (PND 8/10/12), three-chamber social preference test (PND 25), self-grooming (PND 30) and plus maze (PND 40). The cortex (RNA-seq) and hippocampus (WGBS - whole genome bisulfite sequencing) were taken for molecular analysis.

Main results

• Behavior: Autism-like traits (connection/communication, sociality, stereotypy) were observed in males from the GAM-HFD group — that is, when obesity was present only before conception (in oocyte donors). There were no significant changes in obesity only during pregnancy (SUR-HFD). Anxiety did not change. Size of behavioral groups: n=7.
• Transcriptome: in the cortex, "autism clusters" of genes converged on Homer1; in "unaffected" siblings from the same GAM-HFD line, other, probably compensatory modules (stress/apoptosis/metabolism) were activated.
• Epigenetics: there were no global methylation shifts in the hippocampus, but a striking picture was revealed on the alternative Homer1 promoter: in “ASD-classified” mice it was demethylated, in the control it was hypermethylated, and in “resistant” NESTED it was intermediate. This is associated with increased expression of the short, activity-induced isoform of Homer1a, which changes the postsynaptic architecture.

Why is this important?

• The work points to a critical window before pregnancy when maternal metabolic state can set long-term neurodevelopmental trajectories in offspring through epigenetic reprogramming of neuronal genes. This adds to epidemiological signals linking maternal obesity and ASD risk.
• Identification of a specific Homer1/Homer1a axis provides a benchmark for biomarkers and future interventions targeting isoform-specific regulation and synaptic plasticity.

What this does not prove (important caveats)

• This is a limited number mouse model; molecular analyses were performed on a small subset (n=3 per sequencing group), without cell-type resolution. Validation in other strains/ages and longitudinal series is needed.
• IVF/superovulation itself can affect epigenetics, although all groups here underwent the same procedures. Causality at the methylation → behavior level requires functional validation (promoter/isoform manipulation).
• The findings cannot be directly applied to humans: epigenetic topology and vulnerability thresholds differ between species.

Practical notes and what's next

• The medical sense is in preconception prevention: control of weight, insulin resistance, nutrition, and inflammation before planning a pregnancy may be no less important than care during gestation. (This is a conclusion based on the logic of the results; this work does not yet set clinical recommendations for people.)
• Scientific steps: (1) validation of Homer1a signatures in independent models/tissues and at the level of individual cell types; (2) causal tests (alternative promoter methylation editing, optogenetics/chemogenetics of isoforms); (3) search for blood epigenetic proxies for early screening.

Source: Allan NP et al. Pre-Conception Maternal Obesity Confers Autism Spectrum Disorder-like Behaviors in Mice Offspring Through Neuroepigenetic Dysregulation. Cells 14(15):1201, 2025. Open Access. https://doi.org/10.3390/cells14151201