Early-life bisphenol A exposure causes detrimental age-related changes in anxiety, depression, learning, and memory in juvenile and adult male rats: Involvement of NMDAR/PSD-95-PTEN/AKT signaling pathway.

Bisphenol A (BPA) is an endocrine disruptor monomer that is widely used in the manufacturing of epoxy resins and polycarbonate plastics. Several lines of evidence indicate the function of the pre- or perinatally PI3K/AKT signaling pathway in the development of psychiatric disorders. The present study aimed to evaluate for the first time the effect of modifying the NMDAR/PSD-95-PTEN/AKT signaling pathway on behavioral and synaptic plasticity of early-life BPA exposure and its long-lasting influence on juvenile and adulthood stages of development. We investigated the effects of oral BPA doses of 50 and 125 mg/kg/day on the prefrontal cortex (PFC) and hippocampus of male Sprague Dawley rats from postnatal day (PND) 18-60 and PND 18-95, which correspond to juvenile and adolescent stages, respectively. Subsequently, we performed a series of rat behavioral tests, including the open field, elevated plus-maze, forced swimming, and Y-maze. Notably, neurotransmitter levels such as dopamine, serotonin, and gamma-aminobutyric acid, levels of postsynaptic density protein 95 and cAMP response element-binding protein, as well as mRNA levels of N-methyl-D-aspartate receptor subunits, fluctuated between reduction and elevation in the PFC and hippocampus. Furthermore, phosphatase and tensin (PTEN) mRNA and protein levels were upregulated in both brain areas, while PI3K, protein kinase B (AKT) and mammalian target of rapamycin (mTOR) mRNA and protein levels were decreased. Finally, our findings indicate that postnatal BPA exposure promotes long-term anxiety and depressive-like behaviors, as well as cognitive impairment, via modulation of the NMDAR/PSD-95-PTEN/AKT pathway. These findings could help to elucidate the potential developmental and neurobehavioral effects of early-life BPA exposure.