Inhibitory Effects of Bisphenol-A on Neural Stem Cells Proliferation and Differentiation in the Rat Brain Are Dependent on Wnt/β-Catenin Pathway

Neurogenesis, a process of generation of new neurons, occurs throughout the life in the hippocampus and sub-ventricular zone (SVZ). Bisphenol-A (BPA), an endocrine disrupter used as surface coating for packaged food cans, injures the developing and adult brain. However, the effects of BPA on neurogenesis and underlying cellular and molecular mechanism(s) are still unknown. Herein, we studied the effect(s) of prenatal and early postnatal exposure of low dose BPA on Wnt/beta-catenin signaling pathway that controls different steps of neurogenesis such as neural stem cell (NSC) proliferation and neuronal differentiation. Pregnant rats were treated with 4, 40, and 400 mu g BPA/kg body weight orally daily from gestational day 6 to postnatal day 21. Both in vivo and in vitro studies showed that BPA alters NSC proliferation and differentiation. BPA impaired NSC proliferation (5'-bromo-2'-deoxyuridine (BrdU(+)) and nestin(+) cells) and neuronal differentiation (BrdU/doublecortin(+) and BrdU/neuronal nuclei (NeuN(+)) cells) in the hippocampus and SVZ as compared to control. It significantly altered expression/protein levels of neurogenic genes and the Wnt pathway genes in the hippocampus. BPA reduced cellular beta-catenin and p-GSK-3 beta levels and decreased beta-catenin nuclear translocation, and cyclin-D1 and TCF/LEF promoter luciferase activity. Specific activation and blockage of the Wnt pathway suggested involvement of this pathway in BPA-mediated inhibition of neurogenesis. Further, blockage of GSK-3 beta activity by SB415286 and GSK-3 beta small interfering RNA (siRNA) attenuated BPA-induced downregulation of neurogenesis. Overall, these results suggest significant inhibitory effects of BPA on NSC proliferation and differentiation in the rat via the Wnt/beta-catenin signaling pathway.