Maternal Fasting During Early Gestation Induces Epigenetic Alterations and Schizophrenia-Related Phenotypes

Why It Matters

The study provides mechanistic evidence that early‑gestation malnutrition can epigenetically program neurodevelopmental disorders, highlighting a critical window for preventive interventions in human pregnancy.

Key Takeaways

• Early‑gestation fasting reduces maternal glucose and insulin at E5.5.
• Male offspring show reduced prefrontal dendritic spine density.
• Impaired prepulse inhibition and increased anxiety observed in FAST males.
• Bulk RNA‑seq reveals sex‑specific differentially expressed genes in PFC.
• Epigenetic profiling shows widespread DNA methylation changes linked to fasting.

Pulse Analysis

The developmental origins of health and disease (DOHaD) framework has long suggested that prenatal stressors shape lifelong disease risk. Historical cohorts, such as the Dutch Hunger Winter, linked first‑trimester famine exposure to a doubled schizophrenia incidence in male offspring. Yet the molecular pathways translating maternal undernutrition into psychiatric vulnerability have remained elusive. By focusing on the narrow window of global DNA demethylation in early embryos, this research bridges epidemiological observations with concrete epigenetic mechanisms, underscoring the importance of maternal nutrition during conception and early gestation.

In the mouse model, brief 16‑hour fasts on embryonic days 1, 3 and 5 produced transient maternal hypoglycemia without altering total caloric intake. Adult male progeny exhibited hallmark schizophrenia‑like traits: lower dendritic spine density in the medial prefrontal cortex, deficits in prepulse inhibition, and increased anxiety in open‑field and elevated‑plus‑maze tests. Transcriptomic profiling uncovered distinct sets of differentially expressed genes in males versus females, with male brains showing up‑regulation of dopamine‑related pathways (e.g., *Drd2*) and females displaying altered metabolic gene networks. Parallel DNA‑methylation arrays identified thousands of CpG sites reshaped by early fasting, suggesting that nutrient‑driven SAM depletion disrupts the establishment of stable epigenetic marks.

These findings have broad implications for both basic neuroscience and public health policy. They suggest that even short‑term nutritional deficits during the earliest weeks of pregnancy can leave lasting molecular scars that predispose to neuropsychiatric disease, particularly in males. Future work may explore dietary supplementation of methyl donors or timing‑specific interventions to mitigate these epigenetic disruptions. Clinicians and policymakers should consider reinforcing nutritional guidance for women of childbearing age, emphasizing that the first weeks of gestation are a vulnerable period for offspring brain development.