Research Article: Methylmercury Causes Blood-Brain Barrier Damage in Rats via Upregulation of Vascular Endothelial Growth Factor Expression

Date Published: January 24, 2017

Publisher: Public Library of Science

Author(s): Tetsuya Takahashi, Masatake Fujimura, Misaki Koyama, Masato Kanazawa, Fusako Usuki, Masatoyo Nishizawa, Takayoshi Shimohata, Mária A. Deli.

http://doi.org/10.1371/journal.pone.0170623

Abstract

Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity.

Partial Text

Methylmercury (MeHg) is a by-product formed during acetaldehyde synthesis. MeHg also occurs in nature due to the microbial methylation of mercury. Artificially produced MeHg has caused serious environmental problems over the past 60 years in Japan [1],[2]. Although extensive artificial MeHg pollution has been reduced, the naturally occurring environmental form is increasing due to increasing mercury emission into the atmosphere associated with human activities [3]. At toxic exposure levels, MeHg causes central nervous system insults such as Hunter-Russell syndrome [4], Minamata disease [5],[6], and Niigata Minamata disease [7]. Clinical manifestations of MeHg intoxication in adults include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The specific symptoms depend on the location of the lesions induced by MeHg, which often produce damage to the cerebellum and occipital lobes [8]. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated.

Using a rat model of subacute MeHg intoxication, we demonstrated for the first time that MeHg causes BBB damage in vivo. The BBB damage in the cerebellum was confirmed by extravasation of endogenous IgG and decreased expression of RECA-1. In addition, we observed increased expression of VEGF in the cerebellum and occipital lobe in rats exposed to MeHg. VEGF expression was detected in rats exposed to MeHg for 4 weeks mainly in astrocytes, major components of the BBB. These findings are consistent with the observation that edema and hemorrhage are observed in the cerebellum of patients with severe cases of Minamata disease exhibit [20],[21].

 

Source:

http://doi.org/10.1371/journal.pone.0170623

 

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