Oxidatively damaged DNA in DNA repair-deficient and ethanol-exposed fetal brains induces gene dysregulation and mitochondrial dysfunction associated with neurodevelopmental disorders

Oxidatively damaged DNA caused by reactive oxygen species (ROS) in the fetal brain contributes to neurodevelopmental disorders (NDDs), but the mechanism is unclear. We investigated the impact of this DNA damage on the developing fetal brain using a DNA repair-deficient oxoguanine glycosylase 1 (Ogg1) knockout (KO) mouse model, exposed during pregnancy to physiological (saline)- and ethanol (EtOH)-enhanced ROS levels. Oxidatively damaged DNA in saline-exposed Ogg1 KO vs. wild-type (WT) fetal brains was increased, and further enhanced by EtOH exposure. These OGG1-and EtOH-dependent patterns of DNA damage were reflected in: (a) increased gene dysregulation in saline-exposed KO brains, and greatly exacerbated by EtOH, notably in the long-term synaptic potentiation pathway, crucial for learning and memory; (b) impaired mitochondrial metabolism in cultured primary Ogg1 KO neurons; and, (c) sex-dependent learning and memory disorders. These results suggest oxidatively damaged DNA in DNA repair-deficient fetal brains contributes to NDDs by altering gene expression and mitochondrial metabolism.