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Title: Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain

Abstract

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{sub 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;more » 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{sub 2}-isoprostanes levels at all time points. Significant negative correlations were found between F{sub 2}-isoprostanes and GSH, as well as between F{sub 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.« less

Authors:
; ;  [1];  [2];  [3];  [4];  [5];  [6];  [2];  [5];  [7]
  1. Departamento de Bioquimica, Centro de Ciencias Biologicas, Universidade Federal de Santa Catarina, 88040-900, Florianopolis, SC (Brazil)
  2. Departamento de Quimica, Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil)
  3. Departamento de Analises Clinicas e Toxicologicas, Centro de Ciencias da Saude, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil)
  4. Departamento de Ciencias Fisiologicas, Centro de Ciencias Biologicas, Universidade Federal de Santa Catarina, Florianopolis, SC (Brazil)
  5. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (United States)
  6. Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil)
  7. Departamento de Bioquimica, Centro de Ciencias Biologicas, Universidade Federal de Santa Catarina, 88040-900, Florianopolis, SC (Brazil), E-mail: farina@ccb.ufsc.br
Publication Date:
OSTI Identifier:
21077930
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 227; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2007.10.010; PII: S0041-008X(07)00462-0; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; BRAIN; DOSES; DRINKING WATER; GLUTATHIONE; LIPIDS; MERCURY; METHYLMERCURY; MICE; ONTOGENESIS; OXIDATION; PEROXIDASES; PRENATAL EXPOSURE; PYRAZOLINES

Citation Formats

Stringari, James, Nunes, Adriana K.C., Franco, Jeferson L., Bohrer, Denise, Garcia, Solange C., Dafre, Alcir L., Milatovic, Dejan, Souza, Diogo O., Rocha, Joao B.T., Aschner, Michael, and Farina, Marcelo. Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain. United States: N. p., 2008. Web. doi:10.1016/j.taap.2007.10.010.
Stringari, James, Nunes, Adriana K.C., Franco, Jeferson L., Bohrer, Denise, Garcia, Solange C., Dafre, Alcir L., Milatovic, Dejan, Souza, Diogo O., Rocha, Joao B.T., Aschner, Michael, & Farina, Marcelo. Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain. United States. doi:10.1016/j.taap.2007.10.010.
Stringari, James, Nunes, Adriana K.C., Franco, Jeferson L., Bohrer, Denise, Garcia, Solange C., Dafre, Alcir L., Milatovic, Dejan, Souza, Diogo O., Rocha, Joao B.T., Aschner, Michael, and Farina, Marcelo. 2008. "Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain". United States. doi:10.1016/j.taap.2007.10.010.
@article{osti_21077930,
title = {Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain},
author = {Stringari, James and Nunes, Adriana K.C. and Franco, Jeferson L. and Bohrer, Denise and Garcia, Solange C. and Dafre, Alcir L. and Milatovic, Dejan and Souza, Diogo O. and Rocha, Joao B.T. and Aschner, Michael and Farina, Marcelo},
abstractNote = {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{sub 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{sub 2}-isoprostanes levels at all time points. Significant negative correlations were found between F{sub 2}-isoprostanes and GSH, as well as between F{sub 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.},
doi = {10.1016/j.taap.2007.10.010},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 227,
place = {United States},
year = 2008,
month = 2
}
  • Paraquat (1,1'-dimethyl-4,4'-bipyridinium) is a widely used herbicide known to induce skin toxicity. This is thought to be due to oxidative stress resulting from the generation of cytotoxic reactive oxygen intermediates (ROI) during paraquat redox cycling. The skin contains a diverse array of antioxidant enzymes which protect against oxidative stress including superoxide dismutase (SOD), catalase, glutathione peroxidase-1 (GPx-1), heme oxygenase-1 (HO-1), metallothionein-2 (MT-2), and glutathione-S-transferases (GST). In the present studies we compared paraquat redox cycling in primary cultures of undifferentiated and differentiated mouse keratinocytes and determined if this was associated with oxidative stress and altered expression of antioxidant enzymes. We foundmore » that paraquat readily undergoes redox cycling in both undifferentiated and differentiated keratinocytes, generating superoxide anion and hydrogen peroxide as well as increased protein oxidation which was greater in differentiated cells. Paraquat treatment also resulted in increased expression of HO-1, Cu,Zn-SOD, catalase, GSTP1, GSTA3 and GSTA4. However, no major differences in expression of these enzymes were evident between undifferentiated and differentiated cells. In contrast, expression of GSTA1-2 was significantly greater in differentiated relative to undifferentiated cells after paraquat treatment. No changes in expression of MT-2, Mn-SOD, GPx-1, GSTM1 or the microsomal GST's mGST1, mGST2 and mGST3, were observed in response to paraquat. These data demonstrate that paraquat induces oxidative stress in keratinocytes leading to increased expression of antioxidant genes. These intracellular proteins may be important in protecting the skin from paraquat-mediated cytotoxicity.« less
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