Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain
Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain
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DOI：
10.1016/j.taap.2007.10.010
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发表时间：
2008-02-15
影响因子：
3.8
通讯作者：
Farina, Marcelo
中科院分区：
文献类型：
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作者：
Stringari, James;Nunes, Adriana K. C.;Farina, Marcelo
在围产期，中枢神经系统（CNS）对金属极其敏感，包括甲基汞（MeHg）。尽管与甲基汞诱导的发育性神经毒性相关的机制尚不清楚，但一些研究指出谷胱甘肽（GSH）抗氧化系统是该毒物的重要分子靶点。为了扩展我们最近关于甲基汞诱导的谷胱甘肽失衡的发现，本研究旨在评估小鼠在子宫内暴露于甲基汞后的产后早期大脑中谷胱甘肽抗氧化系统的发育情况。怀孕小鼠在妊娠期间暴露于不同剂量的MeHg（1、3和10 mg/l，在饮用水中随意稀释）。分娩后，在不同的时间点（出生后第1、11和21天）杀死幼崽，并使用全脑测定与抗氧化GSH系统相关的生化参数，以及汞含量和f -2-异前列腺素水平。在对照动物中，大脑谷胱甘肽水平在产后早期随着时间的推移而显著增加；妊娠期暴露于甲基汞引起了这一发育事件的剂量依赖性抑制。对照动物产后早期脑谷胱甘肽过氧化物酶（GPx）和谷胱甘肽还原酶（GR）活性随时间显著升高；妊娠期甲基汞暴露对两种发育现象均有剂量依赖性抑制作用。在所有时间点大脑f -2异前列腺素水平的显著增加证实了产前甲基汞暴露的这些不良影响。f -2-异前列腺素与GSH之间以及f -2-异前列腺素与GPx活性之间存在显著负相关，表明甲基汞诱导的GSH系统成熟中断与甲基汞诱导的幼犬脑脂质过氧化增加有关。在子宫内接触甲基汞也导致出生时大脑汞水平呈剂量依赖性增加。即使在出生后第21天大脑汞浓度下降到接近基础水平，甲基汞暴露小鼠的GSH水平、GPx和GR活性仍然下降，这表明产前暴露于甲基汞会通过诱导生化改变影响大脑GSH抗氧化系统，即使汞组织水平下降并且与出生后控制坝的幼崽无法区分。这项研究首次表明，产前暴露于MeHg会破坏小鼠大脑中谷胱甘肽抗氧化系统的产后发育，并指出了MeHg在发育中的中枢神经系统中诱导促氧化损伤的另一种分子机制。此外，我们的实验观察证实了先前关于产前甲基汞暴露后观察到的永久性功能缺陷的报道。(C) 2007爱思唯尔公司版权所有。
During the perinatal period, the central nervous system (CNS) is extremely sensitive to metals, including methylmercury (MeHg). Although the mechanism(s) associated with MeHg-induced developmental neurotoxicity remains obscure, several studies point to the glutathione (GSH) antioxidant system as an important molecular target for this toxicant. To extend our recent findings of MeHg-induced GSH dyshomeostasis, the present study was designed to assess the developmental profile of the GSH antioxidant system in the mouse brain during the early postnatal period after in utero exposure to MeHg. Pregnant mice were exposed to different doses of MeHg (1, 3 and 10 mg/l, diluted in drinking water, ad libitum) during the gestational period. After delivery, pups were killed at different time points - postnatal days (PND) 1, 11 and 21 - and the whole brain was used for determining biochemical parameters related to the antioxidant GSH system, as well as mercury content and the levels of F-2-isoprostane. In control animals, cerebral GSH levels significantly increased over time during the early postnatal period; gestational exposure to MeHg caused a dose-dependent inhibition of this developmental event. Cerebral glutathione peroxidase (GPx) and glutathione reductase (GR) activities significantly increased over time during the early postnatal period in control animals; gestational MeHg exposure induced a dose-dependent inhibitory effect on both developmental phenomena. These adverse effects of prenatal MeHg exposure were corroborated by marked increases in cerebral F-2-isoprostanes levels at all time points. Significant negative correlations were found between F-2-isoprostanes and GSH, as well as between F-2-isoprostanes and GPx activity, suggesting that MeHg-induced disruption of the GSH system maturation is related to MeHg-induced increased lipid peroxidation in the pup brain. In utero MeHg exposure also caused a dose-dependent increase in the cerebral levels of mercury at birth. Even though the cerebral mercury concentration decreased to nearly basal levels at postnatal day 21, GSH levels, GPx and GR activities remained decreased in MeHg-exposed mice, indicating that prenatal exposure to MeHg affects the cerebral GSH antioxidant systems by inducing biochemical alterations that endure even when mercury tissue levels decrease and become indistinguishable from those noted in pups born to control dams. This study is the first to show that prenatal exposure to MeHg disrupts the postnatal development of the glutathione antioxidant system in the mouse brain, pointing to an additional molecular mechanism by which MeHg induces pro-oxidative damage in the developing CNS. Moreover, our experimental observation corroborates previous reports on the permanent functional deficits observed after prenatal MeHg exposure. (C) 2007 Elsevier Inc. All rights reserved.