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(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.
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
authors.forename: James
authors.initials: J
authors.lastname: Stringari
authors.forename: Adriana K C
authors.initials: AK
authors.lastname: Nunes
authors.forename: Jeferson L
authors.initials: JL
authors.lastname: Franco
authors.forename: Denise
authors.initials: D
authors.lastname: Bohrer
authors.forename: Solange C
authors.initials: SC
authors.lastname: Garcia
authors.forename: Alcir L
authors.initials: AL
authors.lastname: Dafre
authors.forename: Dejan
authors.initials: D
authors.lastname: Milatovic
authors.forename: Diogo O
authors.initials: DO
authors.lastname: Souza
authors.forename: João B T
authors.initials: JB
authors.lastname: Rocha
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D008297:Male; D018811:Maternal Exposure; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D018384:Oxidative Stress; D011247:Pregnancy
chemical_list: D008767:Methylmercury Compounds; D005978:Glutathione