The Effect of Prenatal Methylmercury Exposure on the GSH Level and Lipid Peroxidation in the Fetal Brain and Placenta of Mice.

Watanabe, Chiho; Kasanuma, Yuichi; Dejima, Yasushi; Satoh, Hiroshi

doi:10.1620/tjem.187.121

Cited by 12 publications

(5 citation statements)

References 18 publications

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“…Moreover, cerebral isoprostanes have been previously demonstrated to be formed in increased amounts in neuropathological conditions related to oxidative stress (Musiek et al, 2007). The increased cerebral mercury levels observed after the in utero exposure to MeHg are in agreement with other studies on the rapid placental transfer of MeHg from mothers to offspring (Watanabe et al 1999). An intriguing phenomenon observed in our study was the extremely rapid decline of brain mercury levels from birth to weaning (Figure 5; half-life ≅ 10 days).…”

Section: Discussionsupporting

confidence: 92%

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

Stringari

Nunes

Franco

et al. 2008

Toxicology and Applied Pharmacology

192

131

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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.

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Section: Discussionsupporting

confidence: 92%

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

Stringari

Nunes

Franco

et al. 2008

Toxicology and Applied Pharmacology

192

131

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“…Hormones (gonadal steroids, thyroid hormones and glucocorticoids) are implicated in the physiological development and function of the CNS (see Schantz and Widholm, 2001, for review). Nonetheless, some effects similar to those observed as a response to hypothyroidism were detected in fetal brains (Watanabe et al, 1999b). Recent evidence indicates that maternal exposure to low doses of MeHg (5 mg/kg chow) from GD0 to PND10 can disrupt thyroid hormone metabolism in newborn mice, which may lead to an excessive and noxious increase in T3 concentrations in the developing brain (Mori et al, 2006).…”

Section: Hormonesmentioning

confidence: 90%

Neurobehavioural and molecular changes induced by methylmercury exposure during development

et al. 2007

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There is an increasing body of evidence on the possible environmental influence on neurodevelopmental and neurodegenerative disorders. Both experimental and epidemiological studies have demonstrated the distinctive susceptibility of the developing brain to environmental factors such as lead, mercury and polychlorinated biphenyls at levels of exposure that have no detectable effects in adults. Methylmercury (MeHg) has long been known to affect neurodevelopment in both humans and experimental animals. Neurobehavioural effects reported include altered motoric function and memory and learning disabilities. In addition, there is evidence from recent experimental neurodevelopmental studies that MeHg can induce depression-like behaviour. Several mechanisms have been suggested from in vivo- and in vitro-studies, such as effects on neurotransmitter systems, induction of oxidative stress and disruption of microtubules and intracellular calcium homeostasis. Recent in vitro data show that very low levels of MeHg can inhibit neuronal differentiation of neural stem cells. This review summarises what is currently known about the neurodevelopmental effects of MeHg and consider the strength of different experimental approaches to study the effects of environmentally relevant exposure in vivo and in vitro.

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“…Damage to both lysosomal and the mitochondrial membranes by Hg compounds might lead to apoptotic cell death (Dare et al, 2001; Franco et al, 2010). Evidence for Hg compounds eliciting LPO has been extensively reported in both cultured cells and rodent models (Huang et al, 2011; Lin et al, 1996; Martinez et al, 2014; Silva de Paula et al, 2016; Vendrell et al, 2007; Watanabe et al, 1999a; Yin et al, 2007). Several studies demonstrated a link between enhanced LPO and Hg exposure in humans.…”

Section: New Perspectives: Mechanistic-based Biomarkersmentioning

confidence: 99%

“…In addition, LPO has been used for biomonitoring wild-life exposure to MeHg (Berntssen et al, 2003; Hoffman et al, 2005). In these samples, LPO is typically measured by levels of individual LPO species, such as malondialdehyde, or by thiobarbituric acid reactive species (TBARS) assay (Huang et al, 2011; Watanabe et al, 1999a). However, the limitation to the utilization of LPO as a biomarker for Hg exposure lies in the fact that a vast amount of chemicals act via oxidative stress and consequent LPO that this measure could not be reasonably used to address the issue of mercury-related toxicity.…”

Section: New Perspectives: Mechanistic-based Biomarkersmentioning

confidence: 99%

Biomarkers of mercury toxicity: Past, present, and future trends

Branco

Caito

Farina

et al. 2017

Journal of Toxicology and Environmental Health, Part B

167

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Mercury (Hg) toxicity continues to represent a global health concern. Given that human populations are mostly exposed to low chronic levels of mercurial compounds (methylmercury through fish, mercury vapor from dental amalgams, and ethylmercury from vaccines), the need for more sensitive and refined tools to assess the effects and/or susceptibility to adverse metal-mediated health risks remains. Traditional biomarkers, such as hair or blood Hg levels, are practical and provide a reliable measure of exposure, but given intra-population variability, it is difficult to establish accurate cause-effect relationships. It is therefore important to identify and validate biomarkers that are predictive of early adverse effects prior to adverse health outcomes becoming irreversible. This review describes the predominant biomarkers used by toxicologists and epidemiologists to evaluate exposure, effect and susceptibility to Hg compounds, weighing on their advantages and disadvantages. Most importantly, and in light of recent findings on the molecular mechanisms underlying Hg-mediated toxicity, potential novel biomarkers that might be predictive of toxic effect are presented, and the applicability of these parameters in risk assessment is examined.

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The Effect of Prenatal Methylmercury Exposure on the GSH Level and Lipid Peroxidation in the Fetal Brain and Placenta of Mice.

Cited by 12 publications

References 18 publications

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

Neurobehavioural and molecular changes induced by methylmercury exposure during development

Biomarkers of mercury toxicity: Past, present, and future trends

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