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Estrogen receptor independent neurotoxic mechanism ofbisphenol A, an environmental estrogen
Yoot Mo Lee,홍진태,Min Jae Seong,Jae Woong Lee,Yong Kyung Lee,김태명,남상윤,김대중,윤영원,Tae Seong Kim,Soon Young Han 대한수의학회 2007 Journal of Veterinary Science Vol.8 No.1
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) -α and -β, 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 μM). 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-α and ER-β compared with PC12 cells expressing vector alone. In addition, there was no difference observed between BPA and 17-β 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-κB) activation. In addition, ERK-specific inhibitor, PD 98,059, reversed BPA-induced cell death and restored NF-κB 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-κB pathway may be more closely involved in BPA-induced neuronal toxicity.
Bisphenol A에 의한 신경계 세포의 칼슘 항상성 교란 및 세포독성에 미치는 영향
이윷모(Yoot Mo Lee),이상민(Sang Min Lee),손동주(Dong Ju Son),이선영(Sun Young Lee),박혜지(Hye Ji Park),남상윤(Sang Yun Nam),김대중(Dae Joong Kim),윤영원(Young Won Yun),유환수(Hwan Soo Yoo),오기완(Ki Wan Oh),김태성(Tae Seong Kim),한순영( 한국독성학회 2004 Toxicological Research Vol.20 No.3
We previously found that bisphenol A (BPA) caused neurotoxic behavioral alteration.<br/> Since disturbance of calcium homeostasis is an implicated contributor in the neurotoxic mechanism of<br/> environmental toxicants, we investigated whether BPA alters calcium homeostasis. Unlike other neurotoxic<br/> agents which cause increase of intracellular calcium level, BPA decreased [Ca2+]i dose-dependently<br/> in PC12 cells and cortical neuronal cells regardless of the calcium existence in buffer. BPA at<br/> greater concentrations than 100 μM reduced cell viability significantly in both types of cells. BPA also<br/> suppressed L-glutamate (L-type channel activator, 30 mM) and trifluoperazine (calmodulin antagonist,<br/> 30 μM)-induced increase of [Ca2+]i. BPA further lowered caffeine (RYR activator, 100 μM)-decreased<br/> [Ca2+]i, but did not alter dantrolene (RYR inhibitor, 100 μM), heparin (IP3 inhibitor, 200 units/ml) and<br/> xestospongin C (IP3 inhibitor, 5 μM)-decreased [Ca2+]i. Cell viability was not directly related to intracellular<br/> calcium change by bisphenol A that alternation of intracellular calcium may not be a direct causal<br/> factor of BPA-induced neuronal cell death.
Attenuation of Scopolamine-induced Cognitive Dysfunction by Obovatol
최동영,홍진태,이영중,Sun Young Lee,Yoot Mo Lee,Hyun Hee Lee,Im Seop Choi,오기완,한상배,남상윤 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.7
Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly people. The disease is pathologically characterized by extracellular deposition of beta-amyloid peptide (Aβ), cholinergic neurodegeneration and elevation of acetylcholine esterase (AChE) activity in the affected regions. In this study, we investigated the effects of obovatol on memory dysfunction,which was caused by scopolamine. Obovatol (0.2, 0.5 and 1 mg/kg for 7 day) attenuated scopolamine (1 mg/kg, i.p.)-induced amnesia in a dose-dependent manner, as revealed by the Morris water maze test and step-through passive avoidance test. Mechanism studies exhibited that obovatol dose-dependently alleviated scopolamine-induced increase in Aβ generation and β-secretase activity in the cortex and hippocampus. Obovatol also attenuated scopolamine-induced rise in AChE activity in the cortex and hippocampus. Obovatol might rescue scopolamine-mediated impaired learning and memory function by attenuating Aβ accumulation and stabilizing cholinergic neurotransmission, which suggests that the natural compound could be a useful agent for the prevention of the development or progression of AD neurodegeneration.
미성숙 마우스에 Bisphenol A 노출시 신경내분비계에서 에스트로겐 수용체 발현 및 신경행동 변화
성민제(Min Jae Seoung),신임철(Im Cheol Shin),이윷모(Yoot Mo Lee),손동주(Dong Ju Son),송연숙(Youn Sook Song),전계현(Kei Hyun Jeon),김윤배(Yun Bae Kim),이법준(Beum Jun Lee),김대중(Dae Joong Kim),윤영원(Young Won Yun),김태성(Tae Seong K 한국독성학회 2004 Toxicological Research Vol.20 No.3
A large number of chemical pollutants including phthalates, alkylphenolic compounds<br/> and organochlorine pesticides have the ability to disrupt endocrine function in animals, and alter cognitive<br/> function. Because hormone mediated events play an important role in central nervous system<br/> development and function, the changes in cognitive function seem to be mediated by the endocrinelike<br/> action of these chemicals. The present study therefore was designed to investigate effect of<br/> bisphenol A (BPA), an endocrine disrupting chemical on neuro-behavial patterns, and expression of<br/> estrogen receptors and tyrosine hydroxylase, a limiting enzyme of dopamine synthesis pathway. BPA<br/> was treated orally for 3 weeks into 3 week old mice, and then the neuro-behavial patterns (stereotype<br/> behaviors such as jumping rearing and forepaw tremor, climbing behavior, tail flick, rotarod and<br/> locomotor activity), and the expression of estrogen receptors and tyrosine hydroxylase were determined<br/> every 3 week for 9 weeks. During the treatment of BPA, the food uptake and body weight<br/> increase were not significantly changed. BPA resulted in the increased stereotype behaviors (jumping,<br/> rearing and forepaw tremor) 6 or 9 weeks after treatment. The time response to tail flick and<br/> locomotor activity were decreased by the treatment of BPA, whereas the time for rotarod was<br/> increased by the treatment of BPA. The expression of estrogen receptor alpha and beta was<br/> increased in the brain and pituitary gland. Maximum expression was found in the brain after 9 week<br/> of 100 mg/kg BPA treatment and in the pituitary gland after 6 week of 100 mg/kg BPA treatment.<br/> Tyrosine hydroxylase was increased in dose and time dependent manners in the brain but no change<br/> was found in the pituitary gland. The present data show that exposure of BPA in the young mice<br/> could alter expression of estrogen receptors and dopamine synthesis pathway, thereby modulate<br/> neuro-behavial patterns (increase of stereotype behaviors but decrease locomotor activity).