Role of bisphenol A in the aberrant activation of ionotropic glutamate transporters in the cerebral cortex and altered behavioral responses in C57BL/6J mice.

Bisphenol A (BPA) is a widely used endocrine-disrupting chemical that is used to manufacture epoxy resins and polycarbonate plastics. Dietary intake is considered the primary source of human exposure through leaching into food and beverages in contact with storage containers. BPA alters brain function through a wide variety of mechanisms, including oxidative stress, endocrine disruption, developmental toxicity, inflammation, epigenetic modifications, and altered neurotransmission systems. Long-term exposure to even small concentrations of BPA has been associated with neurotoxicity. Mechanistic underpinning of neurotransmitters and free radical-mediated neurotoxicity of BPA is linked with Glutamate (Glu), which plays a vital role in normal brain functioning. Excitatory amino acid transporters (EAATs) play a crucial role in maintaining normal levels of Glu in the synaptic cleft, and EAAT dysfunction leads to excitotoxicity. We studied the effect of oral BPA exposure (40 μg/kg and 400 μg/kg doses) for 60 days in male mice. BPA exposure caused altered spatial learning and deteriorated sensorimotor coordination in exposed animals. These findings were supported by a decrease in acetylcholinesterase (AChE) activity and an increase in monoamine oxidase (MAO), coupled with nitrosative and oxidative overload in the cerebral cortex. A significant upregulation in expression of EAATs and xCT was observed in BPA-treated animals compared to controls at mRNA and protein levels in the cerebral cortex. BPA also caused histopathological changes in the cortical and hippocampal regions of exposed mice. Results of our study prove that even low-dose BPA exposure caused neurotoxicity and altered the expression of Glu-transporters with putative behavioral changes.