title: Estrogen receptor independent neurotoxic mechanism of bisphenol A, an environmental estrogen.
abstract: Bisphenol A (BPA), a ubiquitous environmental contaminant, has been shown to cause developmental toxicity and carcinogenic effects. BPA may have physiological activity through estrogen receptor (ER) -alpha and -beta, which are expressed in the central nervous system. We previously found that exposure of BPA to immature mice resulted in behavioral alternation, suggesting that overexposure of BPA could be neurotoxic. In this study, we further investigated the molecular neurotoxic mechanisms of BPA. BPA increased vulnerability (decrease of cell viability and differentiation, and increase of apoptotic cell death) of undifferentiated PC12 cells and cortical neuronal cells isolated from gestation 18 day rat embryos in a concentration-dependent manner (more than 50 microM). The ER antagonists, ICI 182,780, and tamoxifen, did not block these effects. The cell vulnerability against BPA was not significantly different in the PC12 cells overexpressing ER-alpha and ER-beta compared with PC12 cells expressing vector alone. In addition, there was no difference observed between BPA and 17-beta estradiol, a well-known agonist of ER receptor in the induction of neurotoxic responses. Further study of the mechanism showed that BPA significantly activated extracellular signal-regulated kinase (ERK) but inhibited anti-apoptotic nuclear factor kappa B (NF-kappaB) activation. In addition, ERK-specific inhibitor, PD 98,059, reversed BPA-induced cell death and restored NF-kappaB activity. This study demonstrated that exposure to BPA can cause neuronal cell death which may eventually be related with behavioral alternation in vivo. However, this neurotoxic effect may not be directly mediated through an ER receptor, as an ERK/NF-kappaB pathway may be more closely involved in BPA-induced neuronal toxicity.
authors.affiliation: College of Pharmacy and CBITRC, Chungbuk National University, Cheongju 361-763, Korea.
authors.forename: Yoot Mo
authors.initials: YM
authors.lastname: Lee
authors.forename: Min Jae
authors.initials: MJ
authors.lastname: Seong
authors.forename: Jae Woong
authors.initials: JW
authors.lastname: Lee
authors.forename: Yong Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Tae Myoung
authors.initials: TM
authors.lastname: Kim
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Nam
authors.forename: Dae Joong
authors.initials: DJ
authors.lastname: Kim
authors.forename: Young Won
authors.initials: YW
authors.lastname: Yun
authors.forename: Tae Seong
authors.initials: TS
authors.lastname: Kim
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Han
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005419:Flavonoids / Q000494:pharmacology; D000077267:Fulvestrant; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D010636:Phenols / Q000633:toxicity*; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004958:Estradiol; D004968:Estrogens, Non-Steroidal; D005419:Flavonoids; D000077267:Fulvestrant; D016328:NF-kappa B; D010636:Phenols; D011960:Receptors, Estrogen; D013629:Tamoxifen; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one