Methylmercury exposure during early Xenopus laevis development affects cell proliferation and death but not neural progenitor specification

Huyck, Ryan W.; Nagarkar, Maitreyi D.; Olsen, Nina Veflen; Clamons, Samuel; Saha, Margaret S.

doi:10.1016/j.ntt.2014.11.010

Cited by 15 publications

(14 citation statements)

References 57 publications

(66 reference statements)

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“…Thus, in addition to DNA fragmentation, this low concentration of MeHg showed a deleterious effect on gene replication. This hypothesis may be also supported by a recent study reporting alterations in gene expression during exposure to this heavy metal [ 29 ]. Still, the values of NBr/MNC and NBu/MNC ratios (0.91 and 1.75, respectively) point to the formation of nucleoplasmic bridges as the main process responsible for the presence of micronuclei.…”

Section: Discussionsupporting

confidence: 63%

Is Low Non-Lethal Concentration of Methylmercury Really Safe? A Report on Genotoxicity with Delayed Cell Proliferation

et al. 2016

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Human exposure to relatively low levels of methylmercury is worrying, especially in terms of its genotoxicity. It is currently unknown as to whether exposure to low levels of mercury (below established limits) is safe. Genotoxicity was already shown in lymphocytes, but studies with cells of the CNS (as the main target organ) are scarce. Moreover, disturbances in the cell cycle and cellular proliferation have previously been observed in neuronal cells, but no data are presently available for glial cells. Interestingly, cells of glial origin accumulate higher concentrations of methylmercury than those of neuronal origin. Thus, the aim of this work was to analyze the possible genotoxicity and alterations in the cell cycle and cell proliferation of a glioma cell line (C6) exposed to a low, non-lethal and non-apoptotic methylmercury concentration. Biochemical (mitochondrial activity) and morphological (integrity of the membrane) assessments confirmed the absence of cell death after exposure to 3 μM methylmercury for 24 hours. Even without promoting cell death, this treatment significantly increased genotoxicity markers (DNA fragmentation, micronuclei, nucleoplasmic bridges and nuclear buds). Changes in the cell cycle profile (increased mitotic index and cell populations in the S and G2/M phases) were observed, suggesting arrest of the cycle. This delay in the cycle was followed, 24 hours after methylmercury withdrawal, by a decrease number of viable cells, reduced cellular confluence and increased doubling time of the culture. Our work demonstrates that exposure to a low sublethal concentration of MeHg considered relatively safe according to current limits promotes genotoxicity and disturbances in the proliferation of cells of glial origin with sustained consequences after methylmercury withdrawal. This fact becomes especially important, since this cellular type accumulates more methylmercury than neurons and displays a vital role protecting the CNS, especially in chronic intoxication with this heavy metal.

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Section: Discussionsupporting

confidence: 63%

Is Low Non-Lethal Concentration of Methylmercury Really Safe? A Report on Genotoxicity with Delayed Cell Proliferation

et al. 2016

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“…Apoptotic cells were observed mainly in the mantle layer, the same layer where γ -H2A.X-positive cells were found. This combination of data reinforces the argument that the toxicity of MeHg seems to activate the signaling cascade of programmed cell death or apoptosis in both adult [ 44 – 46 ] and developing CNS [ 6 , 14 , 22 , 35 , 38 ]. Moreover, we proposed that the association between decreased proliferation and increased apoptosis may act as one cause of the reduction in the thickness of the spinal cord layers.…”

Section: Discussionsupporting

confidence: 82%

“…Neural cell proliferation was disturbed by MeHg, as demonstrated by in vitro and in vivo assays [ 14 , 35 , 36 ]. It was also demonstrated that MeHg affects the proliferation in all regions of the developing CNS, such as the spinal cord in Xenopus laevis and Danio rerio [ 37 , 38 ], as well as in the murine brain and cerebellum [ 34 , 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

MeHg Developing Exposure Causes DNA Double-Strand Breaks and Elicits Cell Cycle Arrest in Spinal Cord Cells

Ferreira

Ammar

Bourckhardt

et al. 2015

Journal of Toxicology

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The neurotoxicity caused by methylmercury (MeHg) is well documented; however, the developmental neurotoxicity in spinal cord is still not fully understood. Here we investigated whether MeHg affects the spinal cord layers development. Chicken embryos at E3 were treated in ovo with 0.1 μg MeHg/50 μL saline solution and analyzed at E10. Thus, we performed immunostaining using anti-γ-H2A.X to recognize DNA double-strand breaks and antiphosphohistone H3, anti-p21, and anti-cyclin E to identify cells in proliferation and cell cycle proteins. Also, to identify neuronal cells, we used anti-NeuN and anti-βIII-tubulin antibodies. After the MeHg treatment, we observed the increase on γ-H2A.X in response to DNA damage. MeHg caused a decrease in the proliferating cells and in the thickness of spinal cord layers. Moreover, we verified that MeHg induced an increase in the number of p21-positive cells but did not change the cyclin E-positive cells. A significantly high number of TUNEL-positive cells indicating DNA fragmentation were observed in MeHg-treated embryos. Regarding the neuronal differentiation, MeHg induced a decrease in NeuN expression and did not change the expression of βIII-tubulin. These results showed that in ovo MeHg exposure alters spinal cord development by disturbing the cell proliferation and death, also interfering in early neuronal differentiation.

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“…The toxicity of methylmercury (MeHg) is a well-documented phenomenon; its effect on the developing central nervous system (CNS) has been investigated in humans since the 1970s, following environmental accidents [ 1 – 5 ]. Different experimental models, such as rats ( Rattus norvegicus ) [ 6 – 8 ], mice ( Mus musculus ) [ 9 – 11 ], chicks ( Gallus domesticus ) [ 12 , 13 ], fish ( Danio rerio ) [ 14 ], and amphibians ( Xenopus laevis ) [ 15 ] have also been used to investigate the cytotoxic effects of this organometal. Even at low concentrations MeHg causes cellular damage in the developing CNS that can lead to permanent impairment [ 16 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…Studies of developmental neurotoxicity generally use brain structures (brain, cerebellum, and hippocampus) as an organ model, given the well-documented behavioral (learning and memory deficit) and motor changes caused by MeHg poisoning [ 16 , 17 , 21 , 27 – 29 ]. However, the spinal cord is also an interesting model for neurodevelopmental toxicity studies because its structural organization is less complex than the encephalon and it has fewer tissue layers, allowing observation of the neurotoxic effects on cells at different stages of differentiation [ 14 , 15 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

MeHg Causes Ultrastructural Changes in Mitochondria and Autophagy in the Spinal Cord Cells of Chicken Embryo

Ferreira

Nazari

Müller

2018

Journal of Toxicology

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Methylmercury (MeHg) is a known neurodevelopmental toxicant, which causes changes in various structures of the central nervous system (CNS). However, ultrastructural studies of its effects on the developing CNS are still scarce. Here, we investigated the effect of MeHg on the ultrastructure of the cells in spinal cord layers. Chicken embryos at E3 were treated in ovo with 0.1 μg MeHg/50 μL saline solution and analyzed at E10. Then, we used transmission electron microscopy (TEM) to identify possible damage caused by MeHg to the structures and organelles of the spinal cord cells. After MeHg treatment, we observed, in the spinal cord mantle layer, a significant number of altered mitochondria with external membrane disruptions, crest disorganization, swelling in the mitochondrial matrix, and vacuole formation between the internal and external mitochondrial membranes. We also observed dilations in the Golgi complex and endoplasmic reticulum cisterns and the appearance of myelin-like cytoplasmic inclusions. We observed no difference in the total mitochondria number between the control and MeHg-treated groups. However, the MeHg-treated embryos showed an increased number of altered mitochondria and a decreased number of mitochondrial fusion profiles. Additionally, unusual mitochondrial shapes were found in MeHg-treated embryos as well as autophagic vacuoles similar to mitophagic profiles. In addition, we observed autophagic vacuoles with amorphous, homogeneous, and electron-dense contents, similar to the autophagy. Our results showed, for the first time, the neurotoxic effect of MeHg on the ultrastructure of the developing spinal cord. Using TEM we demonstrate that changes in the endomembrane system, mitochondrial damage, disturbance in mitochondrial dynamics, and increase in mitophagy were caused by MeHg exposure.

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Methylmercury exposure during early Xenopus laevis development affects cell proliferation and death but not neural progenitor specification

Cited by 15 publications

References 57 publications

Is Low Non-Lethal Concentration of Methylmercury Really Safe? A Report on Genotoxicity with Delayed Cell Proliferation

Is Low Non-Lethal Concentration of Methylmercury Really Safe? A Report on Genotoxicity with Delayed Cell Proliferation

MeHg Developing Exposure Causes DNA Double-Strand Breaks and Elicits Cell Cycle Arrest in Spinal Cord Cells

MeHg Causes Ultrastructural Changes in Mitochondria and Autophagy in the Spinal Cord Cells of Chicken Embryo

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