Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction

摘要: Maternal stress is a key risk factor in neurodevelopmental disorders, which often have sex bias severity and prevalence. We previously identified O-GlcNAc transferase (OGT) as placental biomarker our mouse model of early prenatal (EPS), where OGT levels were lower male compared with female tissue further decreased following maternal stress. However, the function programming developing brain has not been determined. Therefore, we generated transgenic targeted disruption Ogt (Pl-OGT) examined offspring for recapitulation adult EPS phenotype. Pl-OGT hemizygous placentas showed similar robust changes gene expression patterns suggestive an altered ability to respond endocrine inflammatory signals, supporting important mediator effects. ChIP-Seq mark 17 beta hydroxysteroid dehydrogenase-3 (Hsd17b3) locus placentas, correlated reduction Hsd17b3 concordant reduced testosterone conversion. Remarkably, had body weights elevated hypothalamic–pituitary–adrenal axis responsivity, recapitulating phenotypes reported males. Further, hypothalamic microarray gene-set enrichment analyses mitochondrial both Cytochrome c oxidase activity assays verified this finding, linking critical programming. Together, these studies confirm demonstrate profound impact single on long-term metabolic that may be related increased disorders.