Effects of Methylmercury on the Microvasculature of the Developing Brain
ABSTRACT The study, undertaken with the aim of further investigating the effects of methylmercury (MeHg) exposure on the developing brain, was performed in the cerebellum of chick embryos, chronically treated with a MeHgCl solution dropped onto the chorioallantoic membrane, and in control embryo cerebella. Quantitative evaluations, performed by cold vapour atomic absorption spectrophotometry, demonstrated a high mercury content in the chorioallantoic membrane, encephalon, liver and kidney of the treated embryos. The morphological observations showed severe neuronal damage consisting of degenerative changes of the granules and Purkinje neurons. The effects on astrocytes were even more severe, since they were extremely rare both in the neuropil and around the vessel wall. Compared with the controls, the cerebellar vessels of MeHg-treated embryos showed immature morphology, poor differentiation of endothelial barrier devices, and high permeability to the exogenous protein horseradish peroxidase. These findings support the hypothesis that MeHg-related neuronal sufferance may be secondary to astrocytic damage and suggest that the developmental neurotoxicity of this compound could also be related to astrocyte loss-dependent impairment of blood-brain barrier (BBB) differentiation.
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- "However, the majority of these studies focus on developmental defects in the postnatal animal, and therefore cannot capture potential responses to toxicity occurring during the earliest phases of neurulation and gene patterning. Research in zebrafish has begun to address this by examining earlier time points in neurodevelopment, and has found a decrease in the proliferation of cells in the neural tube (Bertossi et al., 2004), along with disruption of genes related to oxidative stress and apoptosis (Yang et al., 2007; Ho et al., 2013). "
ABSTRACT: Methylmercury (MeHg) is a widespread environmental toxin that preferentially and adversely affects developing organisms. To investigate the impact of MeHg toxicity on the formation of the vertebrate nervous system at physiologically relevant concentrations, we designed a graded phenotype scale for evaluating Xenopus laevis embryos exposed to MeHg in solution. Embryos displayed a range of abnormalities in response to MeHg, particularly in brain development, which is influenced by both MeHg concentration and the number of embryos per ml of exposure solution. A TC50 of ~50μg/l and LC50 of ~100μg/l were found when maintaining embryos at a density of one per ml, and both increased with increasing embryo density. In situ hybridization and microarray analysis showed no significant change in expression of early neural patterning genes including sox2, en2, or delta; however a noticeable decrease was observed in the terminal neural differentiation genes GAD and xGAT, but not xVGlut. PCNA, a marker for proliferating cells, was negatively correlated with MeHg dose, with a significant reduction in cell number in the forebrain and spinal cord of exposed embryos by tadpole stages. Conversely, the number of apoptotic cells in neural regions detected by a TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay was significantly increased. These results provide evidence that disruption of embryonic neural development by MeHg may not be directly due to a loss of neural progenitor specification and gene transcription, but to a more general decrease in cell proliferation and increase in cell death throughout the developing nervous system. Copyright © 2014. Published by Elsevier Inc.Neurotoxicology and Teratology 12/2014; 47. DOI:10.1016/j.ntt.2014.11.010 · 3.22 Impact Factor
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- "MeHg also alters the molecular homeostasis of the CNS  . According to Bertossi et al. , the cellular damage in the cerebellum of the embryos treated with MeHg support the assertion that this neurotoxin affects the neurons and glial populations through diverse mechanisms. One of the effects on synaptic transmission is the increase and subsequent decrease in the release of a neurotransmitter, such as glutamate. "
ABSTRACT: Previous studies have shown that combined exposure to ethanol (EtOH) and methylmercury (MeHg) in rats during central nervous system development produces several behavioural impairments. This present study was done to investigate inhibitory avoidance acquisition and panic-like disorders in rats in an elevated T-maze (ETM) model of anxiety. Pregnant rats received tap water or EtOH at 22.5% (w/v) (6.5 g/kg per day, by gavage) during pregnancy and lactation. On the 15th day of pregnancy, half of each group received MeHg (8 mg/kg, by gavage). Adult offspring intoxicated by both EtOH + MeHg showed an increase in the ETM re-exposure time. Upon analysis of the enclosed arms latency in baseline and avoidance 1 session it was observed that the rats spent less time inside the arm, suggesting impairment in their short-term memory. The escape latency decreased for EtOH + MeHg and also for EtOH and MeHg groups, suggesting panic-like behaviour. After 24-h and 7-day trials (tests and retests), MeHg and EtOH + MeHg groups had their latency in the enclosed arm reduced with the exception of the EtOH group, revealing memory impairment. Upon analysis of the risk assessment, animals treated with EtOH + MeHg were the only ones to show a decrease in all evaluation stages. This study demonstrates that the exposure to both EtOH and MeHg has an impact on memory and panic-related behaviours, leading to the assertion that this association of toxicants should be studied more in detail to clarify the precise mechanisms of these pharmacological effects.Behavioural brain research 03/2010; 211(2):191-7. DOI:10.1016/j.bbr.2010.03.032 · 3.39 Impact Factor
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- "Given the weak similarities between cerebellum and hippocampus responses to environmental contaminants and the fact that most of the proteins differentially expressed in the 100× MeHg, 100× PCBs or 100× OCs treatment groups were not significantly affected in the 100× NCM treatment group, the few proteins differentially expressed in sub-mixtures and NCM and in both brain structures represent potentially interesting biomarkers of exposure/effects . Two such proteins were identified by MALDI-TOF/TOF MS: Albumin (spot 3 in the cerebellum and 29 in the hippocampus) and Adaptin Ear-Binding Clathrin-Associated Protein 1 (NECAP-1, spots 234 and 262), see Table 4 and Fig. 4. Albumin extravasation has been reported following exposure to MeHg (Bertossi et al., 2004), while PCBs (Slim et al., 2001; Toborek et al., 1995) and organochlorine pesticides (Sinha and Shukla, 2003) have been shown to induce blood-brain barrier dysfunction in vivo or in vitro. Therefore, the increased amounts of albumin detected in cerebellum and hippocampus extracts following exposure to environmental contaminant mixtures may be indicative of perturbation of cerebrovascular permeability. "
ABSTRACT: Human populations are simultaneously exposed to a variety of anthropogenic contaminants. However, despite extensive literature on animal exposure to single compounds, data on the toxicity of complex mixtures are scarce. The Northern Contaminant Mixture (NCM) was formulated to contain the 27 most abundant contaminants in the same relative proportions found in the blood of Canadian Arctic populations. Sprague-Dawley rat dams were dosed from the first day of gestation until weaning with methylmercury (MeHg), polychlorinated biphenyls (PCBs) or organochlorines pesticides (OCs) administered either separately or together in the NCM. An additional control group for hypothyroxinemia was included by dosing dams with the goitrogen 6-propyl-2-thiouracil (PTU). Offspring growth, survival, serum thyroxine and Thyroid Stimulating Hormone (TSH) levels, thyroid gland morphology, brain taurine content and cerebellum and hippocampus protein expression patterns resulting from such exposures were monitored. Pups' increased mortality rate and impaired growth observed in the NCM treatment group were attributed to MeHg, while decreased circulating thyroxine levels and perturbations of thyroid gland morphology were mostly attributable to PCBs. Interestingly, despite comparable reduction in serum thyroxine levels, PCBs and PTU exposures produced markedly different effects on pup's growth, serum TSH level and brain taurine content. Analysis of cerebellum and hippocampus protein expression patterns corroborated previous cerebellum gene expression data, as contaminant co-exposure in the NCM significantly masked the effects of individual components on protein two-dimensional electrophoresis patterns. Identification by MALDI-TOF/TOF MS of differentially expressed proteins involved notably in neuronal and mitochondrial functions provided clues on the cellular and molecular processes affected by these contaminant mixtures.Toxicology Letters 12/2008; 184(3):176-85. DOI:10.1016/j.toxlet.2008.11.004 · 3.36 Impact Factor