Maternal high-fat diet induces sex-dependent alterations in progenitor cell dynamics and impairs neurogenesis in the embryonic mouse cerebral cortex.

High-fat diet (HFD) can disrupt postnatal cortical development leading to the development of neurodevelopmental disorders. Despite that, prenatal effects of maternal HFD for the development of the cerebral cortex remain understudied. This study aimed to determine how early maternal exposure to HFD alters the dynamics of cortical progenitor cells and neurogenesis in a sex-dependent manner during embryonic brain development. Female C57/BL6 mice were exposed to HFD from conception up to 15 days of embryonic development. Immunolabeling analyses were performed at embryonic days 13 (E13) and 15 (E15) to assess progenitor cell dynamics and neurogenesis, and after birth to evaluate longer-term consequences on cortex assembly. Also, placental alterations and cytokine content were analyzed. Results show that acute maternal HFD exposure leads to significant reductions in intermediate progenitors (IPs) population and newly generated neurons (NNs), with sex-dependent variations. Prenatal effects persisted into the postnatal stage, leading to altered cortical structure. Additionally, maternal HFD induced changes in interneuron populations, specifically decreasing somatostatin (SST) interneurons and increasing parvalbumin (PV) interneurons, which are critical for cortical circuit functionality. Maternal HFD also caused sexually dimorphic changes in placental cytokine expression, increasing TNF-α in females and decreasing IL-6 in males, potentially contributing to the observed neurogenesis impairments. These findings underscore the significant impact of maternal nutrition on neurodevelopment, potentially linked with placental and brain adaptations in a sex-dependent manner. We encourage the need for targeted sex-dependent interventions to mitigate these adverse effects.