neurotoxic mechanism of bisphenol A is estrogen-receptor independent - ERK/NF-kB pathway

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free online, mostly technical, but the conclusions are important. BPA

can kill neurons.

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Estrogen receptor independent neurotoxic mechanism of bisphenol A, an

environmental estrogen

Yoot Mo Lee et al.

J Vet Sci. 2007 Mar;8(1):27-38

http://www.vetsci.org/2007/pdf/27.pdf

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) -¥á and -¥â,

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 ¥ìM). 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-¥á and ER-¥â

compared with PC12 cells expressing vector alone. In addition, there was

no difference observed between BPA and 17-¥â 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-¥ê activation. In addition, ERK-specific

inhibitor, PD 98,059, reversed BPA-induced cell death and restored

NF-¥êB 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-kB pathway may be more

closely involved in BPA-induced neuronal toxicity.

Yoot Mo Lee1, Min Jae Seong1, Jae Woong Lee1, Yong Kyung Lee1, Tae

Myoung Kim2, Sang-Yoon Nam2, Dae Joong Kim2, Young Won Yun2, Tae Seong

Kim3, Soon Young Han3, Jin Tae Hong1,*

1College of Pharmacy and CBITRC, and 2College of Veterinary Medicine and

Research Institute of Veterinary Medicine, Chungbuk National University,

Cheongju 361-763, Korea

3National Institute of Toxicological Research, Korea Food and Drug

Administration, Seoul 122-704, Korea

* jinthong@...