Placental lipid droplets and histone marks reveal a metabolic-epigenetic phenotype in the BTBR mouse model of autism.

INTRODUCTION

The placenta shapes fetal brain development through metabolic and epigenetic regulation. The BTBR T+ Itpr3tf/J (BTBR) mouse provides a valuable model of neurodevelopmental vulnerability. This study investigates the cellular and spatial distribution of lipid metabolic and epigenetic alterations within the BTBR placenta.

METHODS

We analyzed mid-gestation (12.5 days post coitum) placentas from BTBR and control (C57BL/6J) mice. Using three-dimensional confocal microscopy and immunohistochemistry, we quantified lipid droplet (LD) architecture, the distribution of the phospholipase PLA2G4E, and specific histone modifications (H3K9 butyrylation and H3K4 trimethylation).

RESULTS

Trophoblast giant cells in BTBR placentas exhibit a marked shift toward smaller lipid droplets, indicating altered lipid remodeling and fragmentation without a reduction in total lipid storage capacity. PLA2G4E displayed conserved, compartment-specific localization across placental layers. At the chromatin level, BTBR placentas showed increased H3K9 butyrylation in trophoblast giant cells and decidua, alongside decreased H3K4 trimethylation in the junctional zone and labyrinth compared to B6 placentas. These integrated metabolic and epigenetic alterations converge primarily within trophoblast giant cells.

CONCLUSION

These findings define a metabolic-epigenetic placental phenotype in the BTBR mouse and support a model in which altered lipid droplet remodeling is associated with distinct chromatin states in key placental cell populations.