Brain-derived neurotrophic factor levels and oxidative stress in autism: evidence from children and a mouse model.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a key factor in neurodevelopment of autism spectrum disorder (ASD), yet the variability of peripheral BDNF levels in ASD remains debated. We sought to investigate the relationship between circulating oxidative stress and peripheral BDNF in children with ASD. METHODS: We analyzed plasma BDNF levels and redox status in both plasma and peripheral blood mononuclear cells (PBMCs) among children with ASD and typically developing (TD) children aged 2-5 years. We generated an autism-like mouse model via prenatal exposure to medroxyprogesterone acetate (MPA). To modulate circulating redox balance, we employed tyrosine kinase-driven lentiviral expression of superoxide dismutase 2 (Sod2) and hematopoietic stem cell (HSC) transplantation with Sod2 overexpression. We then assessed circulating redox balance, gene expression, epigenetic changes, peripheral BDNF levels, and autism-like behaviours in offspring. RESULTS: We included 78 children in the ASD group and 63 children in the TD group. Children with ASD exhibited elevated plasma BDNF levels and an altered redox balance compared with TD controls. In the mouse model, MPA-exposed autism-like offspring demonstrated increased peripheral BDNF levels and heightened oxidative stress in hematopoietic stem cells, endothelial cells, and PBMCs. Tyrosine kinase-Sod2 lentiviral expression in the endothelium fully normalized peripheral BDNF levels, while HSC transplantation with Sod2 overexpression not only reduced plasma BDNF levels, but also alleviated autism-like behaviours. LIMITATIONS: This study's cross-sectional data limit causal inference between oxidative stress and BDNF levels among children with ASD. The mouse model, while informative, may not fully recapitulate human ASD heterogeneity. CONCLUSION: In ASD, elevated peripheral BDNF levels are associated with circulating oxidative stress. Prenatal progestin exposure induces both increased peripheral BDNF and oxidative stress, effects that can be completely reversed through SOD2 modulation in circulation among mouse offspring.