Perinatal BPA Exposure-Associated Depressive-like Behaviors in Male Offspring May Involve Changes in Autophagy-Related Proteins and GABARAP-GABAAR Interaction.

BACKGROUND

Perinatal bisphenol A (BPA) exposure is epidemiologically linked to depressive-like behaviors in offspring, but mechanisms are unclear. Whether autophagy mediates BPA effects and associated transcriptional changes is unknown.

METHODS

Pregnant C57BL/6 mice received BPA (0, 0.2, 2.0 μg/mL) in drinking water from GD0 to PND21. Male offspring were tested for depressive-like behaviors; hippocampal GABA, dopamine, autophagy proteins (p62, LC3-II, GABARAP), and GABARAP-GABAAR colocalization were measured. The autophagy inhibitor 3-MA was used in a 2×2 factorial design. Molecular docking assessed predicted BPA binding at the GABARAP-GABAAR interface. Bulk RNA-seq profiled hippocampal transcriptomes.

RESULTS

BPA exposure was associated with depressive-like behaviors, reduced GABA and dopamine, altered autophagic markers (increased p62/LC3-II, decreased GABARAP/GABAAR), and reduced GABARAP-GABAAR colocalization in the dentate gyrus. 3-MA exacerbated several deficits. Docking predicted stable BPA interaction with the interface. Transcriptomics identified 258 DEGs, with upregulated GABA-related genes (Gabre, Gad2, Abat) and enrichment in synaptic transmission and oxidative phosphorylation.

CONCLUSIONS

Perinatal BPA exposure in male offspring is associated with depressive-like behaviors, autophagy-related marker alterations, GABARAP-GABAAR dissociation, and transcriptional changes in GABAergic pathways. These correlative findings suggest autophagy-related pathways as a potential target for further investigation, but causal mediation and sex-specificity require additional validation.