Sex-dependent preventive effects of prenatal N-acetyl-cysteine on neuronal, emotional and metabolic dysfunctions following exposure to maternal high-fat diet in mice

While a clear association between maternal obesity and an increased risk for neuropsychiatric disorders in the offspring has been described, the underlying mechanisms remain poorly understood. We hypothesised that a maternal high-fat diet (mHFD) would act as a stressor, increasing glucocorticoids, resulting in an altered redox balance and disrupted neuronal plasticity of the limbic system. Such enduring effects would impair the emotional and cognitive profile, neuroendocrine responses, and metabolic and redox homeostasis in the adult offspring. We utilised a mouse model and a translational cellular model employing human neurons derived from inducible Pluripotent Stem Cells (iPSCs) to evaluate the impact of mHFD on neurodevelopment and to test the protection afforded by the antioxidant N-acetyl-cysteine (NAC). Our approach combined behavioural and metabolic phenotyping, biochemical assays, morphological assessment, and targeted gene expression analysis. Results indicate that prenatal administration of NAC prevented anxiety-like and risk-taking behaviours, cognitive impairments and metabolic alterations in mHFD adult mouse offspring, particularly in females. These changes were accompanied by hippocampal downregulation of genes involved in neuronal plasticity, such as BDNF. Using human neurons in vitro, pre-treatment with NAC rescued the negative effects of glucocorticoids on neuronal plasticity via a BDNF-mediated mechanism. The protective effects of NAC over mHFD in females suggest that rebalancing the redox status could be exploited as an overall strategy to buffer the negative effects of early adversities on neurodevelopment.