DELAYED NEUROCHEMICAL EFFECTS OF PRENATAL EXPOSURE TO MeHg IN THE CEREBELLUM OF DEVELOPING RATS (original) (raw)
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Toxicology and Applied Pharmacology, 2008
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 (PNDs) 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 dosedependent 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.
Metabolic Brain Disease, 2013
Methylmercury (MeHg) is a metal toxin found commonly in the environment. Studies have shown severe neurotoxic effects of MeHg poisoning especially during pregnancy where it crosses the foetoplacental and the blood brain barrier of the foetus leading to neurodevelopmental deficits in the offspring. These deficits may predispose offspring to neurodegenerative diseases later in life. In this study we investigated the effects of prenatal methylmercury exposure (2.5 mg/L in drinking water from GND 1-GND 21) on the trace element status in the brain of adolescent offspring (PND 28). Total antioxidant capacity (TAC) was measured in their blood plasma. In a separate group of animals that was also exposed prenatally to MeHg, 6-hydroydopamine (6-OHDA) was administered at PND 60 as a model of neuronal insult. Trace element and TAC levels were compared before and after 6-OHDA exposure. Prenatal MeHg treatment alone resulted in significantly higher concentrations of zinc, copper, manganese and selenium in the brain of offspring at PND 28 (p < 0.05), when compared to controls. In contrast, brain iron levels in MeHg-exposed adolescent offspring were significantly lower than their controls (p <0.05). Following 6-OHDA exposure, the levels of iron, zinc, copper and manganese were increased compared to sham-lesioned offspring (p <0.05). Prenatal MeHg exposure further increased these trace element levels thereby promoting toxicity (p <0.05). Total antioxidant capacity was not significantly different in MeHg and control groups prior to lesion. However, following 6-OHDA administration, MeHg-exposed animals had a significantly lower TAC than that of controls (p <0.05). Brain TAC levels were higher in adult male rats than in female rats during adolescence however male rats that had been exposed to MeHg in utero failed to show this increase at PND 74. Prenatal MeHg exposure results in trace element dyshomeostasis in the brain of offspring and reduces total antioxidant capacity. This may reflect a mechanism by which methylmercury exerts its neurotoxicity and/or predispose offspring to further neurological insults during adulthood.
Toxicological Sciences, 2013
Maternal exposure to the neurotoxin methylmercury (MeHg) has been shown to have adverse effects on neural development of the offspring in man. Little is known about the underlying mechanisms by which MeHg affects the developing brain. To explore the neurodevelopmental defects and the underlying mechanism associated with MeHg exposure, the cerebellum and cerebrum of Wistar rat pups were analyzed by [ 18 F]FDG PET functional imaging, field potential analysis, and microarray gene expression profiling. Female rat pups were exposed to MeHg via maternal diet during intrauterinal and lactational period (from gestational day 6 to postnatal day (PND)10), and their brain tissues were sampled for the analysis at weaning (PND18-21) and adulthood (PND61-70). The [ 18 F]FDG PET imaging and field potential analysis suggested a delay in brain activity and impaired neural function by MeHg. Genome-wide transcriptome analysis substantiated these findings by showing (1) a delay in the onset of gene expression related to neural development, and (2) alterations in pathways related to both structural and functional aspects of nervous system development. The latter included changes in gene expression of developmental regulators, developmental phase-associated genes, small GTPase signaling molecules, and representatives of all processes required for synaptic transmission. These findings were observed at dose levels at which only marginal changes in conventional developmental toxicity endpoints were detected. Therefore, the approaches applied in this study are promising in terms of yielding increased sensitivity compared with classical developmental toxicity tests.
Reproductive Toxicology, 2012
Little is known about the underlying mechanisms by which MeHg affects the developing brain. To explore the neurodevelopmental defects and the underlying mechanism associated with MeHg exposure, the cerebellum and cerebrum of Wistar rat pups were analyzed by [ 18 F]FDG PET functional imaging, field potential analysis, and microarray gene expression profiling. Female rat pups were exposed to MeHg via maternal diet during intrauterinal and lactational period (from gestational day 6 to postnatal day (PND)10), and their brain tissues were sampled for the analysis at weaning (PND18-21) and adulthood (PND61-70). The [ 18 F]FDG PET imaging and field potential analysis suggested a delay in brain activity and impaired neural function by MeHg. Genome-wide transcriptome analysis substantiated these findings by showing (1) a delay in the onset of gene expression related to neural development, and (2) alterations in pathways related to both structural and functional aspects of nervous system development. The latter included changes in gene expression of developmental regulators, developmental phase-associated genes, small GTPase signaling molecules, and representatives of all processes required for synaptic transmission. These findings were observed at dose levels at which only marginal changes in conventional developmental toxicity endpoints were detected. Therefore, the approaches applied in this study are promising in terms of yielding increased sensitivity compared with classical developmental toxicity tests.
In Utero Exposure to Methylmercury and Se Deficiency Converge on the Neurobehavioral Outcome in Mice
Neurotoxicology and Teratology, 1999
In utero exposure to methylmercury and Se deficiency converge on the neurobehavioral outcome in mice . NEUROTOXICOL TERATOL 21 (1) 83-88, 1999.-Pregnant female ICR mice, maintained on torula-based diets containing various amounts of Se (0.02, 0.05, or 0.4 mg/kg diet), were given methylmercury (MeHg; 0, 5, or 9 mgHg/kg in total) on the 12-14th days of gestation. The neurobehavioral function of the offspring born to these dams was evaluated with respect to reflex and motor development, thermal preference, and open-field activity. Se deficiency per se as well as exposure to MeHg exerted additive or synergistic effects on the neurobehavioral functions examined. The group of mice most affected was the group given the lowest amount of Se and the highest dose of MeHg. Thus, the neurobehavioral outcome of in utero MeHg exposure and Se deficiency converged. Although the dietary level of Se did not affect the Hg concentration in the fetal brain, the Se concentration and the activity of glutathione peroxidase, a selenoenzyme, were severely depressed by MeHg in the neural tissue. The possibility that functional Se deficiency by MeHg exposure partly accounts for the neurobehavioral toxicity of MeHg is discussed.
Neurobehavioral toxicity in progeny of rat mothers exposed to methylmercury during gestation
Annali dell'Istituto superiore di sanità, 2014
Methylmercury (MeHg) is recognized as one of the most hazardous environmental pollutants. This may be a concern to long-term consumption of contaminated fish and seafood for health risk to pregnant women and their children. An animal study was conducted to assess the effect of MeHg exposure on rodent offspring following in utero exposure. Pregnant Wister rats were treated by gavage with MeHg at dose levels of 0.5, 1.0 and 2.0 mg/kg/day from gestation day (GD) 5 till parturition, and then were allowed to deliver. Dams treated with 2.0 mg/kg/day MeHg group showed signs of toxicity such as gait alterations and hyperactivity resulting in the failure to deliver sustainable viable pups. MeHg had significant effects on body weight gain of dams during GD 5 till parturition. MeHg had no significant effects on the ages of physical developments such as pinna detachment, incisor eruptions or eye opening as well as alter cliff avoidance, surface righting, swimming ontogeny, startle reflex, pivot...
Archives of toxicology, 2017
In this study, we assessed some hippocampal signaling cascades and behavioral impairments in 30-day-old rat pups prenatally exposed to methylmercury (MeHg). Pregnant rats were exposed to 1.0 or 2.0 mg/kg MeHg by gavage in alternated days from gestational day 5 until parturition. We found increased anxiety-like and decreased exploration behavior evaluated by open field test and deficit of both short- and long-term memories by novel object recognition task, respectively, in MeHg-treated pups. Downregulated PI3K/Akt/mTOR pathway and activated/hypophosphorylated (Ser9) GSK3β in MeHg-treated pups could be upstream of hyperphosphorylated Tau (Ser396) destabilizing microtubules and contributing to neural dysfunction in the hippocampus of these rats. Hyperphosphorylated/activated p38MAPK and downregulated phosphoErk1/2 support a role for mitogen-activated protein kinase (MAPK) cascade on MeHg neurotoxicity. Decreased receptor of advanced glycation end products (RAGE) immunocontent supports ...
Mechanisms of methylmercury-induced neurotoxicity: Evidence from experimental studies
Life Sciences, 2011
Neurological disorders are common, costly, and can cause enduring disability. Although mostly unknown, a few environmental toxicants are recognized causes of neurological disorders and subclinical brain dysfunction. One of the best known neurotoxins is methylmercury (MeHg), a ubiquitous environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. In the aquatic environment, MeHg is accumulated in fish, which represent a major source of human exposure. Although several episodes of MeHg poisoning have contributed to the understanding of the clinical symptoms and histological changes elicited by this neurotoxicant in humans, experimental studies have been pivotal in elucidating the molecular mechanisms that mediate MeHg-induced neurotoxicity. The objective of this mini-review is to summarize data from experimental studies on molecular mechanisms of MeHg-induced neurotoxicity. While the full picture has yet to be unmasked, in vitro approaches based on cultured cells, isolated mitochondria and tissue slices, as well as in vivo studies based mainly on the use of rodents, point to impairment in intracellular calcium homeostasis, alteration of glutamate homeostasis and oxidative stress as important events in MeHg-induced neurotoxicity. The potential relationship among these events is discussed, with particular emphasis on the neurotoxic cycle triggered by MeHg-induced excitotoxicity and oxidative stress. The particular sensitivity of the developing brain to MeHg toxicity, the critical role of selenoproteins and the potential protective role of selenocompounds are also discussed. These concepts provide the biochemical bases to the understanding of MeHg neurotoxicity, contributing to the discovery of endogenous and exogenous molecules that counteract such toxicity and provide efficacious means for ablating this vicious cycle.
Brain Research, 2000
The transplacental neurotoxicity of methylmercury MeHg on the fetal rat brain was studied. Adult female rats were administered 1, 2 Ž. or 3 mgrkgrday methylmercury chloride MMC orally for either 5 or 12 days, and were then mated. They were subsequently administered MMC in the same manner until the end of gestation. On embryonic day 22, a proportion of the fetal brains were histologically examined. Neuronal degeneration of varying degree was detected consistently in the brain stem, cingulate cortex, thalamus and cerebral basal area, including the hypothalamus. The distribution pattern of neuronal damage was different from those in rats treated with MeHg in the postnatal or adult stages. This finding suggests that pathomechanisms in MeHg intoxication operate distinctively in the fetal brain. The offspring derived from dams treated with 1 mgrkgrday MMC for 5 pregestational days and throughout pregnancy survived with inherent brain lesions. This experimental model could be a useful tool for research on the neurotoxicity of MeHg in the human fetal brain.