Growth-promoting effect of bisphenol A on neuroblastoma in vitro and in vivo.
OBJECTIVE
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 17beta-estradiol (E(2); 1 ng/mL), BPA (2 microg/mL) with or without estrogen receptor antagonist ICI182,780 (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 microg/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, tumor 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). ICI182,780 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.
Department of Pediatric Surgery, Children's Hospital, Fudan University, Shanghai 201102, P.R. China.
Haitao
H
Zhu
Xianmin
X
Xiao
Jicui
J
Zheng
Shan
S
Zheng
Kuiran
K
Dong
Yong
Y
Yu
D000704:Analysis of Variance; D000818:Animals; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D051358:Cyclin-Dependent Kinase 4 / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010636:Phenols / Q000494:pharmacology*; D011336:Probability; D011897:Random Allocation; D012680:Sensitivity and Specificity; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D051358:Cyclin-Dependent Kinase 4; D004958:Estradiol; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds