Abstract
Maternal subclinical hypothyroidism (SCH) has been associated with neurodevelopmental disorders, but the molecular mechanisms underlying its impact on offspring behavior remain poorly understood. This study investigates the role of the Wnt/BDNF signaling pathway in the development of autism-like behaviors in male offspring rats born to SCH mothers. Our findings demonstrate that maternal SCH induces significant behavioral abnormalities in the offspring, including increased grooming behavior and deficits in social interaction, which are hallmarks of autism spectrum disorder (ASD). These behaviors correlate with alterations in hippocampal protein expression, particularly a decrease in Brain-Derived Neurotrophic Factor (BDNF) and key signaling molecules involved in neuronal survival, such as cAMP response element-binding protein (CREB) and B-cell lymphoma 2 (Bcl-2). Additionally, we observe a marked upregulation of mTOR gene expression and a downregulation of Wnt signaling in the hippocampus of SCH-exposed offspring. These molecular changes are consistent with disrupted synaptic plasticity and neurogenesis, which are critical processes for cognitive and social development. Our study further reveals that impaired Wnt/BDNF signaling may play a pivotal role in the pathogenesis of autism-like behaviors in these offspring. Moreover, sex-specific differences were observed in the behavioral manifestations, with male offspring showing more pronounced deficits, suggesting a gender-dependent sensitivity to maternal SCH. This research provides novel insights into the molecular pathways by which maternal thyroid dysfunction contributes to neurodevelopmental disorders, offering potential targets for therapeutic intervention.