Growth-promoting effect of bisphenol A on neuroblastoma in vitro and in vivo

Purpose: To investigate the effect and mechanism of bisphenol A (BPA), one of the main environmental endocrine disruptors, on the proliferation of human neuroblastoma cells. Methods: In vitro, cultured SK-N-SH cells were treated with 17 beta-estradiol (E-2; 1 ng/mL), BPA (2 mu g/mL) with or without estrogen receptor antagonist ICII82,780 (10(-6) mol/L). Viable cell number, DNA proliferation index, and expression of cyclin-dependent kinase 4 and cyclin D1 were assessed by absorbance reading, flow cytometry, and western blotting, respectively. In vivo, ovariectomized nude mice bearing SK-N-SH tumors were administered by gavage with E-2 (500 mu g/kg per day, n = 11), BPA (200 mg/kg per day, n = 10), or vehicle (n = 9) for 18 days. Mice body weight, tumor volume and weight were examined every 3 days. Tumor microvessel density, proliferating cell nuclear antigen and vascular endothelial growth factor expression were evaluated by immunohistochemical staining or western blotting. Results: In vitro, the BPA group had 20% higher number of viable cells, 70% higher proliferation index (both P < .01), and higher expression of cyclin-dependent kinase 4 and cyclin D1 than the nontreated group. In vivo, the BPA group had over 50% higher gross tumor volume, turner weight, microvessel density, proliferating cell nuclear antigen (P < .05 or .01), and higher vascular endothelial growth factor protein expression than the mock control group. Both in vitro and in vivo BPA effects were comparable with those by E-2. ICII82,780 effectively abolished the promoting effect for both. Conclusions: Bisphenol A can promote the growth of neuroblastoma to a level similar to that of E-2. Estrogen receptor-dependent pathway and angiogenesis may contribute to the underlying mechanisms. (C) 2009 Elsevier Inc. All rights reserved.