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/β-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 μg 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 β-catenin and p-GSK-3β levels and decreased β-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-3β activity by SB415286 and GSK-3β 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/β-catenin signaling pathway.
Developmental Toxicology Division, Systems Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80-MG Marg, Lucknow, Uttar Pradesh, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Shashi Kant
SK
Tiwari
Developmental Toxicology Division, Systems Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80-MG Marg, Lucknow, Uttar Pradesh, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Swati
S
Agarwal
Developmental Toxicology Division, Systems Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80-MG Marg, Lucknow, Uttar Pradesh, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Brashket
B
Seth
Developmental Toxicology Division, Systems Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80-MG Marg, Lucknow, Uttar Pradesh, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Anuradha
A
Yadav
Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.|Photobiology Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80-MG Marg, Lucknow, Uttar Pradesh, India.
Ratan Singh
RS
Ray
Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Vijay Nath
VN
Mishra
Developmental Toxicology Division, Systems Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 80-MG Marg, Lucknow, Uttar Pradesh, India. rajnish@iitr.res.in.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. rajnish@iitr.res.in.
Rajnish Kumar
RK
Chaturvedi
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D000089662:Doublecortin Protein; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D017208:Rats, Wistar; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D000089662:Doublecortin Protein; D010636:Phenols; D051176:beta Catenin; C495268:Ctnnb1 protein, rat; C000714848:Dcx protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds
Bisphenol-A; Hippocampus; Neural differentiation; Neural stem cells; Wnt/β-catenin pathway