Necrotic-like BV-2 Microglial Cell Death Due to Methylmercury Exposure

Overview

Journal Front Pharmacol

Date 2022 Nov 21

PMID 36408241

Authors

B Martins

J P Novo

E Fonseca

R Raposo

V A Sardao

F Pereira

R B Oria

C Fontes-Ribeiro

J Malva

Affiliations

Soon will be listed here.

Abstract

Methylmercury (MeHg) is a dangerous environmental contaminant with strong bioaccumulation in the food chain and neurotoxic properties. In the nervous system, MeHg may cause neurodevelopment impairment and potentially interfere with immune response, compromising proper control of neuroinflammation and aggravating neurodegeneration. Human populations are exposed to environmental contamination with MeHg, especially in areas with strong mining or industrial activity, raising public health concerns. Taking this into consideration, this work aims to clarify pathways leading to acute toxic effects caused by MeHg exposure in microglial cells. BV-2 mouse microglial cells were incubated with MeHg at different concentrations (0.01, 0.1, 1 and 10 µM) for 1 h prior to continuous Lipopolysaccharide (LPS, 0.5 μg/ml) exposure for 6 or 24 h. After cell exposure, reactive oxygen species (ROS), IL-6 and TNF-α cytokines production, inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) release, metabolic activity, propidium iodide (PI) uptake, caspase-3 and -9 activities and phagocytic activity were assessed. MeHg 10 µM decreased ROS formation, the production and secretion of pro-inflammatory cytokines IL-6, TNF-α, iNOS immunoreactivity, the release of NO in BV-2 cells. Furthermore, MeHg 10 µM decreased the metabolic activity of BV-2 and increased the number of PI-positive cells (necrotic-like cell death) when compared to the respective control group. Besides, MeHg did not interfere with caspase activity or the phagocytic profile of cells. The short-term effects of a high concentration of MeHg on BV-2 microglial cells lead to impaired production of several pro-inflammatory mediators, as well as a higher microglial cell death necrosis, compromising their neuroinflammatory response. Clarifying the mechanisms underlying MeHg-induced neurotoxicity and neurodegeneration in brain cells is relevant to better understand acute and long-term chronic neuroinflammatory responses following MeHg exposure.

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References

Harada M . Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol. 1995; 25(1):1-24. DOI: 10.3109/10408449509089885. View

Yin Z, Jiang H, Syversen T, Rocha J, Farina M, Aschner M . The methylmercury-L-cysteine conjugate is a substrate for the L-type large neutral amino acid transporter. J Neurochem. 2008; 107(4):1083-90. PMC: 2581650. DOI: 10.1111/j.1471-4159.2008.05683.x. View

Eto K . Pathology of Minamata disease. Toxicol Pathol. 1998; 25(6):614-23. DOI: 10.1177/019262339702500612. View

Charleston J, Bolender R, MOTTET N, Body R, Vahter M, Burbacher T . Increases in the number of reactive glia in the visual cortex of Macaca fascicularis following subclinical long-term methyl mercury exposure. Toxicol Appl Pharmacol. 1994; 129(2):196-206. DOI: 10.1006/taap.1994.1244. View

Bassett T, Bach P, Chan H . Effects of methylmercury on the secretion of pro-inflammatory cytokines from primary microglial cells and astrocytes. Neurotoxicology. 2011; 33(2):229-34. DOI: 10.1016/j.neuro.2011.10.003. View

Sierra A, Abiega O, Shahraz A, Neumann H . Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front Cell Neurosci. 2013; 7:6. PMC: 3558702. DOI: 10.3389/fncel.2013.00006. View

Cheng M, Geng Y, Chen Y, Zhang Y, Guo R, Xu H . δ-Opioid receptor activation ameliorates lipopolysaccharide-induced inflammation and apoptosis by inhibiting the MAPK/caspase-3 pathway in BV2 microglial cells. Exp Brain Res. 2020; 239(2):401-412. DOI: 10.1007/s00221-020-05983-9. View

Wang T, Qin L, Liu B, Liu Y, Wilson B, Eling T . Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia. J Neurochem. 2004; 88(4):939-47. DOI: 10.1046/j.1471-4159.2003.02242.x. View

Schaafsma W, Zhang X, van Zomeren K, Jacobs S, Georgieva P, Wolf S . Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing. Brain Behav Immun. 2015; 48:205-21. DOI: 10.1016/j.bbi.2015.03.013. View

10.

Hanisch U, Kettenmann H . Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007; 10(11):1387-94. DOI: 10.1038/nn1997. View

11.

Shinozaki Y, Danjo Y, Koizumi S . Microglial ROCK is essential for chronic methylmercury-induced neurodegeneration. J Neurochem. 2019; 151(1):64-78. DOI: 10.1111/jnc.14817. View

12.

Wang X, Yan M, Zhao L, Wu Q, Wu C, Chang X . Low-Dose Methylmercury-Induced Apoptosis and Mitochondrial DNA Mutation in Human Embryonic Neural Progenitor Cells. Oxid Med Cell Longev. 2016; 2016:5137042. PMC: 4972916. DOI: 10.1155/2016/5137042. View

13.

Wang-Sheng C, Jie A, Jian-Jun L, Lan H, Zeng-Bao X, Chang-Qing L . Piperine attenuates lipopolysaccharide (LPS)-induced inflammatory responses in BV2 microglia. Int Immunopharmacol. 2016; 42:44-48. DOI: 10.1016/j.intimp.2016.11.001. View

14.

Chang J . Methylmercury causes glial IL-6 release. Neurosci Lett. 2007; 416(3):217-20. DOI: 10.1016/j.neulet.2007.01.076. View

15.

Glass C, Saijo K, Winner B, Marchetto M, Gage F . Mechanisms underlying inflammation in neurodegeneration. Cell. 2010; 140(6):918-34. PMC: 2873093. DOI: 10.1016/j.cell.2010.02.016. View

16.

Tian J, Luo Y, Chen W, Yang S, Wang H, Cui J . MeHg Suppressed Neuronal Potency of Hippocampal NSCs Contributing to the Puberal Spatial Memory Deficits. Biol Trace Elem Res. 2016; 172(2):424-436. DOI: 10.1007/s12011-015-0609-8. View

17.

Novo J, Martins B, Raposo R, Pereira F, Oria R, Malva J . Cellular and Molecular Mechanisms Mediating Methylmercury Neurotoxicity and Neuroinflammation. Int J Mol Sci. 2021; 22(6). PMC: 8003103. DOI: 10.3390/ijms22063101. View

18.

Pierozan P, Biasibetti H, Schmitz F, Avila H, Fernandes C, Pessoa-Pureur R . Neurotoxicity of Methylmercury in Isolated Astrocytes and Neurons: the Cytoskeleton as a Main Target. Mol Neurobiol. 2016; 54(8):5752-5767. DOI: 10.1007/s12035-016-0101-2. View

19.

Ni M, Li X, Yin Z, Sidoryk-Wegrzynowicz M, Jiang H, Farina M . Comparative study on the response of rat primary astrocytes and microglia to methylmercury toxicity. Glia. 2011; 59(5):810-20. PMC: 3080116. DOI: 10.1002/glia.21153. View

20.

Moreira A, Branco A, Sampaio S, Cunha-Oliveira T, Martins T, Holy J . Mitochondrial apoptosis-inducing factor is involved in doxorubicin-induced toxicity on H9c2 cardiomyoblasts. Biochim Biophys Acta. 2014; 1842(12 Pt A):2468-78. DOI: 10.1016/j.bbadis.2014.09.015. View