Skip to main content
SpringerLink
Log in

Astrocyte-Like Cells Transcriptome Changes After Exposure to a Low and Non-cytotoxic MeHg Concentration

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

The central nervous system is the main target of MeHg toxicity and glial cells are the first line of defense; however, their true role remains unclear. This study aimed to identify the global map of human glial-like (U87) cells transcriptome after exposure to a non-toxic and non-lethal MeHg concentration and to investigate the related molecular changes. U87 cells were exposed upon 0.1, 0.5, and 1 µM MeHg for 4 and 24 h. Although no changes were observed in the percentage of viable cells, the metabolic viability was significantly decreased after exposure to 1 µM MeHg for 24 h; thus, the non-toxic concentration of 0.1 µM MeHg was chosen to perform microarray analysis. Significant changes in U87 cells transcriptome were observed only after 24 h. The expression of 392 genes was down regulated while 431 genes were up-regulated. Gene ontology showed alterations in biological processes (75%), cellular components (21%), and molecular functions (4%). The main pathways showed by KEGG and Reactome were cell cycle regulation and Rho GTPase signaling. The complex mechanism of U87 cells response against MeHg exposure indicates that even a low and non-toxic concentration is able to alter the gene expression profile.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

All quantitative data used to support these findings are included in this article.

References

  1. Hong YS, Kim YM, Lee KE (2012) Methylmercury exposure and health effects. j prev med public health. J Prev Med Public Health 45:353. https://doi.org/10.3961/jpmph.2012.45.6.353

    Article  Google Scholar 

  2. WHO (2014). Public health impacts of exposure to mercury and mercury compounds: the role of who and ministries of public health in the implementation of the minamata convention. 67th World Health Assembly. 24 may 2014. https://apps.who.int/iris/handle/10665/158953

  3. Farina M, Aschner M, Rocha JB (2011) Oxidative stress in MeHg-induced neurotoxicity. Toxicol Appl Pharmacol 256:405–417. https://doi.org/10.1016/j.taap.2011.05.001

    Article  CAS  Google Scholar 

  4. Aschner M, Syversen T, Souza DO, Rocha JB, Farina M (2007) Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity. Braz J Med Biol Res 40(3):285–291. https://doi.org/10.1590/s0100-879x2007000300001 (PMID: 17334523)

    Article  CAS  Google Scholar 

  5. Unoki T, Akiyama M, Kumagai Y, Gonçalves FM, Farina M, da Rocha JBT, Aschner M (2018) Molecular pathways associated with methylmercury-induced Nrf2 modulation. Front Genet 12(9):373. https://doi.org/10.3389/fgene.2018.00373.PMID:30271424;PMCID:PMC6146031

    Article  Google Scholar 

  6. Oliveira RAA, Pinto BD, Rebouças BH, Ciampi de Andrade D, Vasconcellos ACS, Basta PC (2021) Neurological impacts of chronic methylmercury exposure in Munduruku indigenous adults: somatosensory, motor, and cognitive abnormalities. Int J Environ Res Public Health 18(19):10270. https://doi.org/10.3390/ijerph181910270 (Published 2021 Sep 29)

    Article  CAS  Google Scholar 

  7. Hargreaves RJ, Foster JR, Pelling D, Moorhouse SR, Gangolli SD, Rowland IR (1985) Changes in the distribution of histochemically localized mercury in the cns and in tissue levels of organic and inorganic mercury during the development of intoxication in methylmercury treated rats. Neuropathol Appl Neurobiol 11:383–401. https://doi.org/10.1111/j.1365-2990.1985.tb00034.x

    Article  CAS  Google Scholar 

  8. Leyshon-Sørland K, Jasani B, Morgan AJ (1994) The localization of mercury and metallothionein in the cerebellum of rats experimentally exposed to methylmercury. Histochem J 26:161–169. https://doi.org/10.1007/BF00157965

    Article  Google Scholar 

  9. Charleston JS, Bolender RP, Mottet NK, Body RL, Vahter ME, Burbacher TM (1994) Increases in the number of reactive glia in the visual cortex of Macaca fascicularis following subclinical long-term methyl mercury exposure. Toxicol Appl Pharmacol 129:196–206. https://doi.org/10.1006/taap.1994.1244

    Article  CAS  Google Scholar 

  10. Chung RS, Adlard PA, Dittmann J, Vickers JC, Chuah MI, West AK (2004) Neuron-glia communication: metallothionein expression is specifically up-regulated by astrocytes in response to neuronal injury. J Neurochem 88:454–461. https://doi.org/10.1046/j.1471-4159.2003.02193.x

    Article  CAS  Google Scholar 

  11. Morken TS, Sonnewald U, Aschner M, Syversen T (2005) Effects of methylmercury on primary brain cells in mono-and co-culture. Toxicol Sci 87:169–175. https://doi.org/10.1093/toxsci/kfi227

    Article  CAS  Google Scholar 

  12. Ni M, Li X, Rocha JB, Farina M, Aschner M (2012) Glia and methylmercury neurotoxicity. J Toxicol Environ Health A 75:1091–1101. https://doi.org/10.1080/15287394.2012.697840

    Article  CAS  Google Scholar 

  13. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. https://doi.org/10.1007/s00401-009-0619-8

    Article  Google Scholar 

  14. Shanker G, Syversen T, Aschner M (2003) Astrocyte-mediated methylmercury neurotoxicity. Biol Trace Elem Res 95:1–10. https://doi.org/10.1385/BTER:95:1:1

    Article  CAS  Google Scholar 

  15. Ben Haim L, Rowitch DH (2017) Functional diversity of astrocytes in neural circuit regulation. Nat Rev Neurosci 18:31–41

    Article  Google Scholar 

  16. Shanker G, Aschner M (2001) Identification and characterization of uptake systems for cystine and cysteine in cultured astrocytes and neurons: evidence for methylmercury-targeted disruption of astrocyte transport. J Neurosci Res 66:998–1002. https://doi.org/10.1002/jnr.10066

    Article  CAS  Google Scholar 

  17. Wang L, Jiang H, Yin Z, Aschner M, Cai J (2009) Methylmercury toxicity and nrf2-dependent detoxification in astrocytes. Toxicological Science 107:135–143. https://doi.org/10.1093/toxsci/kfn201

    Article  CAS  Google Scholar 

  18. Noguchi Y, Shinozaki Y, Fujishita K, Shibata K, Imura Y, Morizawa Y, Gachet C, Koizumi S (2013) Astrocytes protect neurons against methylmercury via atp/p2y1 receptor-mediated pathways in astrocytes. PLoS ONE 8:e57898. https://doi.org/10.1371/journal.pone.0057898

    Article  CAS  Google Scholar 

  19. Malik N, Wang X, Shah S, Efthymiou AG, Yan B, Heman-Ackah S, Zhan M, Rao M (2014) Comparison of the gene expression profiles of human fetal cortical astrocytes with pluripotent stem cell derived neural stem cells identifies human astrocyte markers and signaling pathways and transcription factors active in human astrocytes. PLoS ONE 9:e96139. https://doi.org/10.1371/journal.pone.0096139

    Article  CAS  Google Scholar 

  20. Caito S, Zeng H, Aschner JL, Aschner M (2014) Methylmercury alters the activities of hsp90 client proteins, prostaglandin e synthase/p23 (pges/23) and nnos. PLoS ONE 9:e98161. https://doi.org/10.1371/journal.pone.0098161

    Article  CAS  Google Scholar 

  21. Pieper I, Wehe CA, Bornhorst J, Ebert F, Leffers L, Holtkamp M, Höseler P, Weber T, Mangerich A, Bürkle A, Karst U, Schwerdtle T (2014) Mechanisms of Hg species induced toxicity in cultured human astrocytes: genotoxicity and DNA-damage response. Metallomics 6:662–671. https://doi.org/10.1039/c3mt00337j

    Article  CAS  Google Scholar 

  22. Oliveira CS, Segatto ALA, Nogara PA, Piccoli BC, Loreto ÉLS, Aschner M, Rocha JBT (2020) Transcriptomic and proteomic tools in the study of hg toxicity: what is missing? Front Genet 11:425. https://doi.org/10.3389/fgene.2020.00425

    Article  CAS  Google Scholar 

  23. Crespo-Lopez ME, Costa-Malaquias A, Oliveira EH, Miranda MS, Arrifano GP, Souza-Monteiro JR, Sagica FE, Fontes-Junior EA, Maia CS, Macchi BM, Donascimento JL (2016) Is low non-lethal concentration of methylmercury really safe? A report on genotoxicity with delayed cell proliferation. Plos One 11:e0162822. https://doi.org/10.1371/journal.pone.0162822

    Article  CAS  Google Scholar 

  24. Vendrell I, Carrascal M, Vilaró MT, Abián J, Rodríguez-Farré E, Suñol C (2007) Cell viability and proteomic analysis in cultured neurons exposed to methylmercury. Hum Exp Toxicol 26:263–272. https://doi.org/10.1177/0960327106070455

    Article  CAS  Google Scholar 

  25. Fujimura M, Usuki F (2012) Differing effects of toxicants (methylmercury, inorganic mercury, lead, amyloid beta, and rotenone) on cultured rat cerebrocortical neurons: differential expression of rho proteins associated with neurotoxicity. Toxicol Sci 126:506–514. https://doi.org/10.1093/toxsci/kfr352

    Article  CAS  Google Scholar 

  26. Petroni D, Tsai J, Agrawal K, Mondal D, George W (2012) Low-dose methylmercury-induced oxidative stress, cytotoxicity, and tau-hyperphosphorylation in human neuroblastoma (shsy5y) cells. Environ Toxicol 27:549–555. https://doi.org/10.1002/tox.20672

    Article  CAS  Google Scholar 

  27. Kong HK, Wong MH, Chan HM, Lo SC (2012) Chronic exposure of adult rats to low doses of methylmercury induced a state of metabolic deficit in the somatosensory cortex. J Proteome Res 12:5233–5245. https://doi.org/10.1021/pr400356v

    Article  CAS  Google Scholar 

  28. Fujimura M, Usuki F (2015) Methylmercury causes neuronal cell death through the suppression of the trka pathway: in vitro and in vivo effects of trka pathway activators. Toxicol Appl Pharmacol 282:259–266. https://doi.org/10.1016/j.taap.2014.12.008

    Article  CAS  Google Scholar 

  29. Bittencourt LO, Puty B, Charone S, Aragão WAB, Farias-Junior PM, Silva MCF, Crespo-Lopez ME, Leite AL, Buzalaf MAR, Lima RR (2017). Oxidative biochemistry disbalance and changes on proteomic profile in salivary glands of rats induced by chronic exposure to methylmercury. Oxidative medicine and cellular longevity 2017. https://doi.org/10.1155/2017/

  30. Mora-Zamorano FX, Klingler R, Basu N, Head J, Murphy CA, Binkowski FP, Larson JK, Carvan MJ 3rd (2017) Developmental methylmercury exposure affects swimming behavior and foraging efficiency of yellow perch (Perca flavescens) larvae. ACS Omega 2:4870–4877. https://doi.org/10.1021/acsomega.7b00227

    Article  CAS  Google Scholar 

  31. Spulber S, Raciti M, Dulko-Smith B, Lupu D, Rüegg J, Nam K, Ceccatelli S (2018) Methylmercury interferes with glucocorticoid receptor: potential role in the mediation of developmental neurotoxicity. Toxicol Appl Pharmacol 354:94–100. https://doi.org/10.1016/j.taap.2018.02.021

    Article  CAS  Google Scholar 

  32. Hernández AJA, Reyes VL, Albores-García D, Gómez R, Calderón-Aranda ES (2018) MeHg affects the activation of FAK, Src, Rac1 and Cdc42, critical proteins for cell movement in PDGF-stimulated SH-SY5Y neuroblastoma cells. Toxicology 396:35–44. https://doi.org/10.1016/j.tox.2017.11.019

    Article  CAS  Google Scholar 

  33. Malthankar GV, White BK, Bhushan A, Daniels CK, Rodnick KJ, Lai JC (2004) Differential lowering by manganese treatment of activities of glycolytic and tricarboxylic acid (tca) cycle enzymes investigated in neuroblastoma and astrocytoma cells is associated with manganese-induced cell death. Neurochem Res 29:709–717. https://doi.org/10.1023/b:nere.0000018841.98399.ce

    Article  CAS  Google Scholar 

  34. Merker K, Hapke D, Reckzeh K, Schmidt H, Lochs H, Grune T (2005) Copper related toxic effects on cellular protein metabolism in human astrocytes. BioFactors 24:1–4. https://doi.org/10.1002/biof.5520240130

    Article  Google Scholar 

  35. Dukhande VV, Malthankar-Phatak GH, Hugus JJ, Daniels CK, Lai JC (2006) Manganese-induced neurotoxicity is differentially enhanced by glutathione depletion in astrocytoma and neuroblastoma cells. Neurochem Res 31:1349–1357. https://doi.org/10.1007/s11064-006-9179-7

    Article  CAS  Google Scholar 

  36. Pennie WD, Tugwood JD, Oliver GJ, Kimber I (2000) The principles and practice of toxigenomics: applications and opportunities. Toxicol Sci 54:277–283. https://doi.org/10.1093/toxsci/54.2.277

    Article  CAS  Google Scholar 

  37. Wildsmith and Spence (2003). Preparation and utilization of microarrays. InAn Introduction to Toxicogenomics, ed. Burczynski (Boca Raton: CRC Press). 3–16

  38. North M, Vulpe CD (2010) Functional toxicogenomics: mechanism-centered toxicology. Int J Mol Sci 11:4796–4813. https://doi.org/10.3390/ijms11124796

    Article  CAS  Google Scholar 

  39. Mahapatra CT, Bond J, Rand DM, Rand MD (2010) Identification of methylmercury tolerance gene candidates in drosophila. Toxicol Sci 160:225–238. https://doi.org/10.1093/toxsci/kfq097

    Article  CAS  Google Scholar 

  40. Richter CA, Garcia-Reyero N, Martyniuk C, Knoebl I, Pope M, Wright-Osment MK, Denslow ND, Tillitt DE (2011) Gene expression changes in female zebrafish (Danio rerio) brain in response to acute exposure to methylmercury. Environ Toxicol Chem 30:01–308. https://doi.org/10.1002/etc.409

    Article  CAS  Google Scholar 

  41. Ho NY, Yang L, Legradi J, Armant O, Takamiya M, Rastegar S, Strähle U (2013) Gene responses in the central nervous system of zebrafish embryos exposed to the neurotoxicant methyl mercury. Environ Sci Technol 47:3316–3325. https://doi.org/10.1021/es3050967

    Article  CAS  Google Scholar 

  42. Montgomery SL, Vorojeikina D, Huang W, Mackay TF, Anholt RR, Rand MD (2014) Genome-wide association analysis of tolerance to methylmercury toxicity in drosophila implicates myogenic and neuromuscular developmental pathways. PLoS ONE 9:e110375. https://doi.org/10.1371/journal.pone.0110375

    Article  CAS  Google Scholar 

  43. Huyck RW, Nagarkar M, Olsen N, Clamons SE, Saha MS (2015) Methylmercury exposure during early xenopus laevis development affects cell proliferation and death but not neural progenitor specification. Neurotoxicol Teratol 47:102–113. https://doi.org/10.1016/j.ntt.2014.11.010

    Article  CAS  Google Scholar 

  44. Graves SD, Kidd KA, Batchelar KL, Cowie AM, O’Driscoll NJ, Martyniuk CJ (2017) Response of oxidative stress transcripts in the brain of wild yellow perch (Perca flavescens) exposed to an environmental gradient of methylmercury. Comp Biochem Physiol C: Toxicol Pharmacol 192:50–58. https://doi.org/10.1016/j.cbpc.2016.12.005

    Article  CAS  Google Scholar 

  45. Toyama T, Yoshida E, Shinkai Y, Kumagai Y (2011) DNA microarray analysis of human neuroblastoma Sh-SY5Y cells exposed to methylmercury. J Toxicol Sci 36:843–845. https://doi.org/10.2131/jts.36.843

    Article  CAS  Google Scholar 

  46. Krug AK, Kolde R, Gaspar JA, Rempel E, Balmer NV, Meganathan K, Vojnits K, Baquié M, Waldmann T et al (2013) Human embryonic stem cell-derivedtest systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol 87:123–143. https://doi.org/10.1007/s00204-012-0967-3

    Article  CAS  Google Scholar 

  47. Waldmann T, Grinberg M, König A, Rempel E, Schildknecht S, Henry M, Holzer AK, Dreser N, Shinde V, Sachinidis A, Rahnenführer J, Hengstler JG, Leist M (2017) Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol 30:905–922. https://doi.org/10.1021/acs.chemrestox.6b00259

    Article  CAS  Google Scholar 

  48. Beauvais-Flück R, Slaveykova VI, Cosio C.(2018). Effects of two-hour exposure to environmental and high concentrations of methylmercury on the transcriptome of the macrophyte Elodea nuttallii. Aquatic Toxicology 194. https://doi.org/10.1016/j.aquatox.2017.11.010

  49. Lansens P, Meuleman C, Baeyens W (1990) Long-term stability of methylmercury standard solutions in distilled, deionized water. Analytica chimica acta 229:281–285. https://doi.org/10.1016/S0003-2670(00)85140-5

    Article  CAS  Google Scholar 

  50. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. https://doi.org/10.1016/0022-1759(83)90303-4

    Article  CAS  Google Scholar 

  51. Rai Y, Pathak R, Kumari N, Sah DK, Pandey S, Kalra N, Soni R, Dwarakanath BS, Bhatt AN (2018) Mitochondrial biogenesis and metabolic hyperactivation limits the application of mtt assay in the estimation of radiation induced growth inhibition. Sci Rep 8:1–15. https://doi.org/10.1038/s41598-018-19930-w

    Article  CAS  Google Scholar 

  52. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal statistical society: series B (Methodological) 57:289–300

    Google Scholar 

  53. Aschner M, Syversen T (2005) Methylmercury: recent advances in the understanding of its neurotoxicity. Ther Drug Monit 27(3):278–283. https://doi.org/10.1097/01.ftd.0000160275.85450.32

    Article  Google Scholar 

  54. Freire MAM, Santana LNS, Bittencourt LO et al (2019) Methylmercury intoxication and cortical ischemia: pre-clinical study of their comorbidity. Ecotoxicol Environ Saf 174:557–565. https://doi.org/10.1016/j.ecoenv.2019.03.009 (PMID: 30865911)

    Article  CAS  Google Scholar 

  55. Bittencourt LO, Dionizio A, Nascimento PC, Puty B, Leão LKR, Luz DA, Silva MCF, Amado LL, Leite A, Buzalaf MR, Crespo-Lopez ME, Maia CSF, Lima RR (2019) Proteomic approach underlying the hippocampal neurodegeneration caused by low doses of methylmercury after long-term exposure in adult rats. Metallomics 11(2):390–403. https://doi.org/10.1039/c8mt00297e (PMID: 30525157)

    Article  CAS  Google Scholar 

  56. Santana LNDS, Bittencourt LO, Nascimento PC, Fernandes RM, Teixeira FB, Fernandes LMP, Freitas Silva MC, Nogueira LS, Amado LL, Crespo-Lopez ME, Maia CDSF, Lima RR (2019) Low doses of methylmercury exposure during adulthood in rats display oxidative stress, neurodegeneration in the motor cortex and lead to impairment of motor skills. J Trace Elem Med Biol 51:19–27. https://doi.org/10.1016/j.jtemb.2018.09.004 (Epub 2018 Sep 11 PMID: 30466930)

    Article  CAS  Google Scholar 

  57. Freire MAM, Lima RR, Nascimento PC, Gomes-Leal W, Pereira A Jr (2020) Effects of methylmercury on the pattern of NADPH diaphorase expression and astrocytic activation in the rat. Ecotoxicol Environ Saf. 201:110799. https://doi.org/10.1016/j.ecoenv.2020.110799 (Epub 2020 Jun 13. PMID: 32544743)

    Article  CAS  Google Scholar 

  58. Song MO, Li J, Freedman JH (2009) Physiological and toxicological transcriptome changes in hepg2 cells exposed to copper. Physiol Genomics 38:386–401. https://doi.org/10.1152/physiolgenomics.00083.2009

    Article  CAS  Google Scholar 

  59. Zimmermann LT, Santos DB, Naime AA, Leal RB, Dórea JG, Barbosa F Jr, Aschner M, Rocha JB, Farina M (2013) Comparative study on methyl-and ethylmercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake. Neurotoxicology 38:1–8. https://doi.org/10.1016/j.neuro.2013.05.015

    Article  CAS  Google Scholar 

  60. Maués LA, Macchi BM, Crespo-López ME, Nasciutti LE, Picanço-Diniz DL, Antunes-Rodrigues J, Nascimento JL (2015). Methylmercury inhibits prolactin release in a cell line of pituitary origin. Brazilian Journal of Medical and Biological Research 48. https://doi.org/10.1590/1414-431X20154165

  61. Robinson JF, Theunissen PT, van Dartel DA, Pennings JL, Faustman EM, Piersma AH (2011) Comparison of MeHg-induced toxicogenomic responses across in vivo and in vitro models used in developmental toxicology. Reprod Toxicol 32:180–188. https://doi.org/10.1016/j.reprotox.2011.05.011

    Article  CAS  Google Scholar 

  62. Jebbett NJ, Hamilton JW, Rand MD, Eckenstein F (2013) Low level methylmercury enhances CNTF-evoked STAT3 signaling and glial differentiation in cultured cortical progenitor cells. Neurotoxicology 38:91–100. https://doi.org/10.1016/j.neuro.2013.06.008

    Article  CAS  Google Scholar 

  63. Guida N, Laudati G, Anzilotti S, Sirabella R, Cuomo O, Brancaccio P, Santopaolo M, Galgani M, Montuori P, Di Renzo G, Canzoniero LM, Formisano L (2016) Methylmercury upregulates re-1silencing transcription factor (rest) in SH-SY5Y cells and mouse cerebellum. Neurotoxicology 52:89–97. https://doi.org/10.1016/j.neuro.2015.11.007

    Article  CAS  Google Scholar 

  64. Wang S, Lv Q, Yang Y, Guo LH, Wan B, Ren X, Zhang H (2016) Arginine decarboxylase: a novel biological target of mercury compounds identified in pc12 cells. Biochem Pharmacol 118:109–120

    Article  CAS  Google Scholar 

  65. Hwang GW, Naganuma A (2006) DNA microarray analysis of transcriptional responses of human neuroblastoma imr-32 cells to methylmercury. J Toxicol Sci 31:537–538. https://doi.org/10.2131/jts.31.537

    Article  CAS  Google Scholar 

  66. Vojnits K, Ensenat-Waser R, Gaspar JA, Meganathan K, Jagtap S, Hescheler J, Sachinidis A, Bremer-Hoffmann S (2012) A tanscriptomics study to elucidate the toxicological mechanism of methylmercury chloride in a human stem cell based in vitro test. Curr Med Chem 19:6224–6232

    CAS  Google Scholar 

  67. Nogueira LS, Vasconcelos CP, Mitre GP, da Silva Kataoka MS, Lima MO, de Oliveira EHC, Lima RR (2019). Oxidative damage in human periodontal ligament fibroblast (hPLF) after methylmercury exposure. Oxidative medicine and cellular longevity 2019. https://doi.org/10.1155/2019/8470857

  68. Castilhos Z, Rodrigues-Filho S, Cesar R, Rodrigues AP, Villas-Bôas R, de Jesus I, Lima M, Faial K, Miranda A, Brabo E, Beinhoff C, Santos E (2015) Human exposure and risk assessment associated with mercury contamination in artisanal gold mining areas in the brazilian amazon. Environ Sci Pollut Res 22:11255–11264

    Article  CAS  Google Scholar 

  69. Crespo-López ME, Macêdo GL, Pereira SI, Arrifano GP, Picanço-Diniz DL, do Nascimento JL, Herculano AM. Pharmacological research 60, 212–220. https://doi.org/10.1016/j.phrs.2009.02.01

  70. Ni M, Li X, Yin Z, Jiang H, Sidoryk-Wegrzynowicz M, Milatovic D, Cai J, Aschner M (2010) Methylmercury induces acute oxidative stress, altering Nrf2 protein level in primary microglial cells. Toxicol Sci 116:590–603. https://doi.org/10.1093/toxsci/kfq126

    Article  CAS  Google Scholar 

  71. Kaur P, Aschner M, Syversen T (2011). Biochemical factors modulating cellular neurotoxicity of methylmercury. Journal of toxicology 2011. https://doi.org/10.1155/2011/721987

  72. Yamada H, Koizumi S (2002) DNA microarray analysis of human gene expression induced by a non-lethal dose of cadmium. Ind Health 40:159–166. https://doi.org/10.2486/indhealth.40.159

    Article  CAS  Google Scholar 

  73. Wang A, Crowley DE (2005) Global gene expression responses to cadmium toxicity in Escherichia coli. J Bacteriol 187:3259–3266. https://doi.org/10.1128/JB.187.9.3259-3266.2005

    Article  CAS  Google Scholar 

  74. Cui Y, McBride SJ, Boyd WA, Alper S, Freedman JH (2007) Toxicogenomic analysis of Caenorhabditis elegans reveals novel genes and pathways involved in the resistance to cadmium toxicity. Genome Biol 8:1–15. https://doi.org/10.1186/gb-2007-8-6-r122

    Article  CAS  Google Scholar 

  75. Sahu SC (2016) Altered global gene expression profiles in human gastrointestinal epithelial Caco2 cells exposed to nanosilver. Toxicol Rep 3:262–268. https://doi.org/10.1016/j.toxrep.2016.01.012

    Article  CAS  Google Scholar 

  76. Diana Neely M, Xie S, Prince LM, Kim H, Tukker AM, Aschner M, Thimmapuram J, Bowman AB (2021). Single cell rna sequencing detects persistent cell type- and methylmercury exposure paradigm-specific effects in a human cortical neurodevelopmental model. Food and Chemical Toxicology , 112288doi: https://doi.org/10.1016/j.fct.2021.112288

  77. Prince LM, Neely MD, Warren EB, Thomas MG, Henley MR, Smith KK, Aschner M, Bowman AB (2021) Environmentally relevant developmental methylmercury exposures alter neuronal differentiation in a human-induced pluripotent stem cell model. Food and Chemical Toxicology 152:112178. https://doi.org/10.1016/j.fct.2021.112178

    Article  CAS  Google Scholar 

  78. Krewski D, Acosta D Jr, Andersen M, Anderson H, Bailar JC 3rd, Boekelheide K et al (2010) Toxicity testing in the 21st century: a vision and a strategy. Journal of Toxicology and Environmental Health, Part B 13:51–138. https://doi.org/10.1080/10937404.2010.483176

    Article  CAS  Google Scholar 

  79. Sanfeliu C, Sebastià J, Ki SU (2001) Methylmercury neurotoxicity in cultures of human neurons, astrocytes, neuroblastoma cells. Neurotoxicology 22:317–327. https://doi.org/10.1016/s0161-813x(01)00015-8

    Article  CAS  Google Scholar 

  80. Waters MD, Fostel JM (2004) Toxicogenomics and systems toxicology: aims and prospects. Nat Rev Genet 5:936–948. https://doi.org/10.1038/nrg1493

    Article  CAS  Google Scholar 

  81. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. Nat Genet 25:25–29. https://doi.org/10.1038/75556

    Article  CAS  Google Scholar 

  82. Stoiber T, Bonacker D, Böhm KJ, Bolt HM, Thier R, Degen GH, Unger E (2004) Disturbed microtubule function and induction of micronuclei by chelate complexes of mercury (ii). Mutation Research/Genetic Toxicology and Environmental Mutagenesis 563:97–106. https://doi.org/10.1016/j.mrgentox.2004.06.009

    Article  CAS  Google Scholar 

  83. Pierozan P, Biasibetti H, Schmitz F, Ávila H, Fernandes CG, Pessoa-Pureur R, Wyse ATS (2017) Neurotoxicity of methylmercury in isolated astrocytes and neurons: the cytoskeleton as a main target. Molecular neurobiology 54:5752–5767. https://doi.org/10.1007/s12035-016-0101-2

    Article  CAS  Google Scholar 

  84. Zheng XH, Watts GS, Vaught S, Gandolfi AJ (2003) Low-level arsenite induced gene expression in HEK293 cells. Toxicology 187:39–48. https://doi.org/10.1016/s0300-483x(03)00025-8

    Article  CAS  Google Scholar 

  85. Hanagata N, Zhuang F, Connolly S, Li J, Ogawa N, Xu M (2011) Molecular responses of human lung epithelial cells to the toxicity of copper oxide nanoparticles inferred from whole genome expression analysis. ACS Nano 5:9326–9338. https://doi.org/10.1021/nn202966t

    Article  CAS  Google Scholar 

  86. Lee JY, Tokumoto M, Hwang GW, Lee MY, Satoh M (2017) Identification of ARNT-regulated BIRC3 as the target factor in cadmium renal toxicity. Sci Rep 7:1–16. https://doi.org/10.1038/s41598-017-17494-9

    Article  CAS  Google Scholar 

  87. Sager PR, Doherty RA, Olmsted JB (1983) Interaction of methylmercury with microtubules in cultured cells and in vitro. Exp Cell Res 146:127–213. https://doi.org/10.1016/0014-4827(83)90331-2

    Article  CAS  Google Scholar 

  88. Castoldi AF, Barni S, Turin I, Gandini C, Manzo L (2000) Early acute necrosis, delayed apoptosis and cytoskeletal breakdown in cultured cerebellar granule neurons exposed to methylmercury. J Neurosci Res 59:775–787. https://doi.org/10.1002/(SICI)1097-4547(20000315)59:6(775:AID-JNR10)3.0.CO;2-T

    Article  CAS  Google Scholar 

  89. Antunes Dos Santos A, Appel Hort M, Culbreth M, López-Granero C, Farina M, Rocha JB, Aschner M (2016) Methylmercury and brain development: a review of recent literature. J Trace Elem Med Biol 38:99–107. https://doi.org/10.1016/j.jtemb.2016.03.001

    Article  CAS  Google Scholar 

  90. Fujimura M, Usuki F, Sawada M, Rostene W, Godefroy D, Takashima A (2009) Methylmercury exposure downregulates the expression of racl and leads to neuritic degeneration and ultimately apoptosis in cerebrocortical neurons. Neurotoxicology 30:16–22. https://doi.org/10.1016/j.neuro.2008.10.002

    Article  CAS  Google Scholar 

  91. Stankiewicz TR, Linseman DA (2014) Rho family GTPases: key players in neuronal development, neuronal survival, and neurodegeneration. Front Cell Neurosci 8:314. https://doi.org/10.3389/fncel.2014.00314

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by the Brazilian Agency for Support and Evaluation of Graduate Education, CAPES and to Brazilian National Council for Scientific and Technological Development (CNPq). The authors are grateful for the support provided by the Pró-Reitoria de Pesquisa e Pós-graduação from the Federal University of Pará and Evandro Chagas Institute.

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)-Finance Code 001. Bruna Puty was supported by Programa Nacional de Pós-Graduação (PNPD/CAPES).

Author information

Authors and Affiliations

  1. Laboratory of Functional and Structural Biology, Institute of Biological Science, Federal University of Pará, Belém, Brazil

    Bruna Puty, Leonardo Oliveira Bittencourt & Rafael Rodrigues Lima

  2. Laboratory of Tissue Culture and Cytogenetics, Environmental Section, Evandro Chagas Institute, Ananindeua, Brazil

    Bruna Puty & Edivaldo Herculano Corrêa de Oliveira

  3. National Institute of Science and Technology in Stem Cell and Cell Therapy (INCT/CNPq) and Center for Cell-Based Therapy, CEPID/FAPESP, Ribeirão Preto, Brazil

    Jéssica Rodrigues Plaça

Authors
  1. Bruna Puty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonardo Oliveira Bittencourt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jéssica Rodrigues Plaça
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edivaldo Herculano Corrêa de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rafael Rodrigues Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: BP, EO, RL; Method: BP; Formal analysis: BP, LB, and JP; T Writing original draft: BP, LB, and RL; Supervision and Writing — review and editing: EO, RL

Corresponding author

Correspondence to Rafael Rodrigues Lima.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 50 kb)

Supplementary file2 (XLSX 11 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Puty, B., Bittencourt, L., Plaça, J. et al. Astrocyte-Like Cells Transcriptome Changes After Exposure to a Low and Non-cytotoxic MeHg Concentration. Biol Trace Elem Res 201, 1151–1162 (2023). https://doi.org/10.1007/s12011-022-03225-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-022-03225-3

Keywords

Search

Navigation