Methylmercury and brain development: A review of recent literature

Santos, Alessandra Antunes dos; Hort, Mariana Appel; Culbreth, Megan; López-Granero, Caridad; Farina, Marcelo; Rocha, João Batista Teixeira da; Aschner, Michael

doi:10.1016/j.jtemb.2016.03.001

Cited by 144 publications

(51 citation statements)

References 145 publications

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“…Similar results have been reported in animal models of brain development after exposure to MeHg in utero [8,9]. Moreover, extensive evidence has demonstrated that MeHg can lead to neural cell death, as well as to cytoarchitectural alterations in the nervous system [10,11,12,13,14]. There is an abundance of knowledge regarding reactive oxygen species (ROS) and especially effects of low-level MeHg exposure on cell cycle regulators in neural stem cells in vitro and in vivo [15,16,17].…”

Section: Introductionsupporting

confidence: 75%

Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

Wang

Yan

Zhao

et al. 2016

IJMS

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Mitochondria are essential organelles and important targets for environmental pollutants. The detection of mitochondrial biogenesis and generation of reactive oxygen species (ROS) and p53 levels following low-dose methylmercury (MeHg) exposure could expand our understanding of underlying mechanisms. Here, the sensitivity of immortalized human neural progenitor cells (ihNPCs) upon exposure to MeHg was investigated. We found that MeHg altered cell viability and the number of 5-ethynyl-2′-deoxyuridine (EdU)-positive cells. We also observed that low-dose MeHg exposure increased the mRNA expression of cell cycle regulators. We observed that MeHg induced ROS production in a dose-dependent manner. In addition, mRNA levels of peroxisome-proliferator-activated receptor gammacoactivator-1α (PGC-1α), mitochondrial transcription factor A (TFAM) and p53-controlled ribonucleotide reductase (p53R2) were significantly elevated, which were correlated with the increase of mitochondrial DNA (mtDNA) copy number at a concentration as low as 10 nM. Moreover, we examined the expression of microRNAs (miRNAs) known as regulatory miRNAs of p53 (i.e., miR-30d, miR-1285, miR-25). We found that the expression of these miRNAs was significantly downregulated upon MeHg treatment. Furthermore, the overexpression of miR-25 resulted in significantly reducted p53 protein levels and decreased mRNA expression of genes involved in mitochondrial biogenesis regulation. Taken together, these results demonstrated that MeHg could induce developmental neurotoxicity in ihNPCs through altering mitochondrial functions and the expression of miRNA.

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Section: Introductionsupporting

confidence: 75%

Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

Wang

Yan

Zhao

et al. 2016

IJMS

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“…It is well known that ROS mediate MeHg-induced neurotoxicity in several experimental models, and mitochondrial changes may initiate a cascade of events culminating in cell death (apoptosis or necrosis) Bernardi et al, 1998;Kroemer and Reed, 2000;Yin et al, 2011). At present, several investigators reported that apoptosis occurs as result of organic Hg-mediated toxicity (dos Santos et al, 2016;Sokolowski et al, 2011;Ceccatelli et al, 2010), but the molecular mechanisms are not fully elucidated. Evidence indicates that Ca 2+ is linked to this neurotoxic effect.…”

Section: Discussionmentioning

confidence: 99%

A brain proteome profile in rats exposed to methylmercury or thimerosal (ethylmercury)

Souza

Marco

Laure

et al. 2016

Journal of Toxicology and Environmental Health, Part A

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Exposure to organomercurials has been associated with harmful effects on the central nervous system (CNS). However, the mechanisms underlying organomercurial-mediated neurotoxic effects need to be elucidated. Exposure to toxic elements may promote cellular modifications such as alterations in protein synthesis in an attempt to protect tissues and organs from damage. In this context, the use of a "proteomic profile" is an important tool to identify potential early biomarkers or targets indicative of neurotoxicity. The aim of this study was to investigate potential modifications in rat cerebral cell proteome following exposure to methylmercury (MeHg) or ethylmercury (EtHg). For MeHg exposure, animals were administered by gavage daily 140 µg/kg/d of Hg (as MeHg) for 60 d and sacrificed 24 h after the last treatment. For EtHg exposure, 800 µg/kg/d of Hg (as EtHg) was given intramuscularly (im) in a single dose and rats were sacrificed after 4 h. Control groups received saline either by gavage or im. After extraction of proteins from whole brain samples and separation by two-dimensional electrophoresis (2-DE), 26 differentially expressed proteins were identified from exposed animals by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF/TOF). Both MeHg and EtHg exposure induced an overexpression of calbindin, a protein that acts as a neuroprotective agent by (1) adjusting the concentration of Ca(2+) within cells and preventing neurodegenerative diseases and (2) decreasing expression of glutamine synthetase, a crucial protein involved in regulation of glutamate concentration in synaptic cleft. In contrast, expression of superoxide dismutase (SOD), a protein involved in antioxidant defense, was elevated in brain of MeHg-exposed animals. Taken together, our data provide new valuable information on the possible molecular mechanisms associated with MeHg- and EtHg-mediated toxicity in cerebral tissue. These observed protein alterations may be considered as biomarkers candidates for biological monitoring of organomercurial poisoning.

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“…Methylmercury (MeHg) is a global environmental contaminant targeting the central nervous system (CNS) (Farina and Aschner 2017;Santos et al 2016). Consumption of MeHg-containing fish products (Canuel et al 2006;Carrasco et al 2011;Steuerwald et al 2000;Stopford and Goldwater 1975) and rice (Rothenberg et al 2014;Zhang et al 2010) has been shown to induce neurodegeneration as well as be associated with neurodevelopmental disorders (Belletti et al 2002;Carocci et al 2014;Ceccatelli et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Acute Methylmercury Exposure and the Hypoxia-Inducible Factor-1α Signaling Pathway under Normoxic Conditions in the Rat Brain and Astrocytes in Vitro

Chang

Yang

Zhou

et al. 2019

Environ Health Perspect

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BACKGROUND: As a ubiquitous environmental pollutant, methylmercury (MeHg) induces toxic effects in the nervous system, one of its main targets. However, the exact mechanisms of its neurotoxicity have not been fully elucidated. Hypoxia-inducible factor-1a (HIF-1a), a transcription factor, plays a crucial role in adaptive and cytoprotective responses in cells and is involved in cell survival, proliferation, apoptosis, inflammation, angiogenesis, glucose metabolism, erythropoiesis, and other physiological activities. OBJECTIVES: The aim of this study was to explore the role of HIF-1a in response to acute MeHg exposure in rat brain and primary cultured astrocytes to improve understanding of the mechanisms of MeHg-induced neurotoxicity and the development of effective neuroprotective strategies. METHODS: Primary rat astrocytes were treated with MeHg (0-10 lM) for 0:5 h. Cell proliferation and cytotoxicity were assessed with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl diphenyltetrazolium bromide (MTT) assay and a lactate dehydrogenase (LDH) release assay, respectively. Reactive oxygen species (ROS) levels were analyzed to assess the level of oxidative stress using 2 0 ,7 0-dichlorofluorescin diacetate (DCFH-DA) fluorescence. HIF-1a, and its downstream proteins, glucose transporter 1 (GLUT-1), erythropoietin (EPO), and vascular endothelial growth factor A (VEGF-A) were analyzed by means of Western blotting. Real-time PCR was used to detect the expression of HIF-1a mRNA. Pretreatment with protein synthesis inhibitor (CHX), proteasome inhibitor (MG132), or proline hydroxylase inhibitor (DHB) were applied to explore the possible mechanisms of HIF-1a inhibition by MeHg. To investigate the role of HIF-1a in MeHg-induced neurotoxicity, cobalt chloride (CoCl 2), 2-methoxyestradiol (2-MeOE2), small interfering RNA (siRNA) transfection and adenovirus overexpression were used. Pretreatment with N-acetyl-L-cysteine (NAC) and vitamin E (Trolox) were used to investigate the putative role of oxidative stress in MeHg-induced alterations in HIF-1a levels. The expression of HIF-1a and related downstream proteins was detected in adult rat brain exposed to MeHg (0-10 mg=kg) for 0:5 h in vivo. RESULTS: MeHg caused lower cell proliferation and higher cytotoxicity in primary rat astrocytes in a time-and concentration-dependent manner. In comparison with the control cells, exposure to 10 lM MeHg for 0:5 h significantly inhibited the expression of astrocytic HIF-1a, and the downstream genes GLUT-1, EPO, and VEGF-A (p < 0:05), in the absence of a significant decrease in HIF-1a mRNA levels. When protein synthesis was inhibited by CHX, MeHg promoted the degradation rate of HIF-1a. MG132 and DHB significantly blocked the MeHg-induced decrease in HIF-1a expression (p < 0:05). Overexpression of HIF-1a significantly attenuated the decline in MeHg-induced cell proliferation, whereas the inhibition of HIF-1a significantly increased the decline in cell proliferation (p < 0:05). NAC and Trolox, two established antioxidants, reversed the MeHg-induced decl...

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Methylmercury and brain development: A review of recent literature

Cited by 144 publications

References 145 publications

Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

A brain proteome profile in rats exposed to methylmercury or thimerosal (ethylmercury)

Acute Methylmercury Exposure and the Hypoxia-Inducible Factor-1α Signaling Pathway under Normoxic Conditions in the Rat Brain and Astrocytes in Vitro

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