DOI QR코드

DOI QR Code

Oral methylmercury intoxication aggravates cardiovascular risk factors and accelerates atherosclerosis lesion development in ApoE knockout and C57BL/6 mice

  • Silva, Janayne L. (Departamento de Bioquimica e Imunologia ICB/UFMG Caixa Postal 486) ;
  • Leocadio, Paola C.L. (Departamento de Nutricao e Saude, Universidade Federal de Minas Gerais) ;
  • Reis, Jonas M. (Departamento de Bioquimica e Imunologia ICB/UFMG Caixa Postal 486) ;
  • Campos, Gianne P. (Departamento de Fisiologia e Biofisica, Universidade Federal de Minas Gerais) ;
  • Capettini, Luciano S.A. (Departamento de Fisiologia e Biofisica, Universidade Federal de Minas Gerais) ;
  • Foureaux, Giselle (Departamento de Morfologia, Universidade Federal de Minas Gerais) ;
  • Ferreira, Anderson J. (Departamento de Morfologia, Universidade Federal de Minas Gerais) ;
  • Windmoller, Claudia C. (Departamento de Quimica, Universidade Federal de Minas Gerais) ;
  • Santos, Flavia A. (Departamento de Morfologia, Universidade Federal Do Ceara) ;
  • Oria, Reinaldo B. (Departamento de Morfologia, Universidade Federal Do Ceara) ;
  • Crespo-Lopez, Maria E. (Instituto de Ciencias Biologicas, Universidade Federal do Para) ;
  • Alvarez-Leite, Jacqueline I. (Departamento de Bioquimica e Imunologia ICB/UFMG Caixa Postal 486)
  • Received : 2020.07.12
  • Accepted : 2020.09.23
  • Published : 2021.07.15

Abstract

Methylmercury (MeHg) intoxication is associated with hypertension, hypercholesterolemia, and atherosclerosis by mechanisms that are not yet fully understood. We investigated the effects of MeHg intoxication in atherosclerosis-prone (ApoE-KO) and resistant C57BL/6 mice. Mice were submitted to carotid stenosis surgery (to induce atherosclerosis faster) and received water or MeHg solution (20 mg/L) for 15 days. Tail plethysmography was performed before and after MeHg exposure. Food and MeHg solution intakes were monitored weekly. On the 15th day, mice were submitted to intravital fluorescence microscopy of mesenteric vasculature to observe in vivo leukocyte rolling and adhesion. Results showed that despite the high hair and liver Hg concentrations in the MeHg group, food and water (or MeHg solution) consumption and liver function marker levels were similar to those in controls. MeHg exposure increased total cholesterol, the atherogenic (non-HDL) fraction and systolic and diastolic blood pressure. MeHg exposure also induced inflammation, as seen by the increased rolling and adhered leukocytes in the mesenteric vasculature. Atherosclerosis lesions were more extensive in the aorta and carotid sites of MeHg-ApoE knockout mice. Surprisingly, MeHg exposure also induced atherosclerosis lesions in C57BL/6 mice, which are resistant to atherosclerosis formation. We concluded that MeHg intoxication might represent a risk for cardiovascular diseases since it accelerates atherogenesis by exacerbating several independent risk factors.

Keywords

Acknowledgement

The authors acknowledge the financial support of the Brazilian National Council for Scientific and Technological Development (CNPq), Coordination for the Improvement of Higher Education Personnel (CAPES) PROCAD 88881.068408/2014-01. The authors also thank the Image Acquisition and Processing Center (CAPI-ICB/UFMG) for the use of imaging equipment.

References

  1. World Health Organization (2017) Mercury and health. WHO Publishing Fact Sheets. https://www.who.int/news-room/fact-sheets/detail/mercury-and-health. Accessed 06 July 2020
  2. Berzas Nevado JJ, Rodriguez Martin-Doimeadios RC, Guzman Bernardo FJ, Jimenez Moreno M, Herculano AM, do Nascimento JLM, Crespo-Lopez ME (2010) Mercury in the Tapajos River basin, Brazilian Amazon: a review. Environ Int 36:593-608. https://doi.org/10.1016/j.envint.2010.03.011
  3. Basu D, Hu Y, Huggins LA, Mullick AE, Graham MJ, Wietecha T, Barnhart S, Mogul A, Pfeiffer K, Zirlik A, Fisher EA, Bornfeldt KE, Willecke F, Goldberg IJ (2018) Novel reversible model of atherosclerosis and regression using oligonucleotide regulation of the LDL receptor. Circ Res 122:560-567. https://doi.org/10.1161/CIRCRESAHA.117.311361
  4. Sharma BM, Sanka O, Kalina J, Scheringer M (2019) An overview of worldwide and regional time trends in total mercury levels in human blood and breast milk from 1966 to 2015 and their associations with health effects. Environ Int 125:300-319. https://doi.org/10.1016/j.envint.2018.12.016
  5. Martin-Doimeadios RCR, Berzas Nevado JJ, Guzman Bernardo FJ, Jimenez Moreno M, Arrifano GPF, Herculano AM, do Nascimento JLM, Crespo-Lopez ME (2014) Comparative study of mercury speciation in commercial fishes of the Brazilian Amazon. Environ Sci Pollut Res Int 21:7466-7479. https://doi.org/10.1007/s11356-014-2680-7
  6. Hong YS, Kim DS, Yu SD et al (2013) Four cases of abnormal neuropsychological findings in children with high blood methylmercury concentrations. Ann Occup Environ Med 25:18. https://doi.org/10.1186/2052-4374-25-18
  7. Clarkson TW, Magos L (2006) The toxicology of mercury and its chemical compounds. Crit Rev Toxicol 36:609-662. https://doi.org/10.1080/10408440600845619
  8. Arrifano GPF, Alvarez-Leite JI, Souza-Monteiro JR, Augusto-Oliveira M, Paraense R, Macchi BM, Pinto A, Oria RB, do Nascimento JLM, Crespo-Lopez ME (2018) In the heart of the Amazon: noncommunicable diseases and apolipoprotein E4 genotype in the riverine population. Int J Environ Res Public Health 15:1957. https://doi.org/10.3390/ijerph15091957
  9. Inoue S, Yorifuji T, Tsuda T, Doi H (2012) Short-term effect of severe exposure to methylmercury on atherosclerotic heart disease and hypertension mortality in Minamata. Sci Total Environ 417-418:291-293. https://doi.org/10.1016/j.scitotenv.2011.11.076
  10. Tamashiro H, Akagi H, Arakaki M, Futatsuka M, Roht LH (1984) Causes of death in Minamata disease: analysis of death certificates. Int Arch Occup Environ Health 54:135-146. https://doi.org/10.1007/BF00378516
  11. Takahashi T, Shimohata T (2019) Vascular dysfunction induced by mercury exposure. Int J Mol Sci 20:1-12. https://doi.org/10.3390/ijms20102435
  12. Islam MZ, Van Dao C, Shiraishi M, Miyamoto A (2016) Methylmercury affects cerebrovascular reactivity to angiotensin II and acetylcholine via Rho-kinase and nitric oxide pathways in mice. Life Sci 147:30-38. https://doi.org/10.1016/j.lfs.2016.01.033
  13. Wells EM, Herbstman JB, Lin YH, Hibbeln JR, Halden RU, Witter FR, Goldman LR (2017) Methyl mercury, but not inorganic mercury, associated with higher blood pressure during pregnancy. Environ Res 154:247-252. https://doi.org/10.1016/j.envres.2017.01.013
  14. Hu XF, Singh K, Chan LHM (2018) Mercury exposure, blood pressure, and hypertension: A systematic review and dose-response meta-analysis. Environ Health Perspect 126:1-15. https://doi.org/10.1289/EHP2863
  15. Moreira EL, Oliveira J, Dutra MF, Santos DB, Goncalves CA, Goldfeder EM, De bem AF, Prediger RD, Aschner M, Farina M, (2012) Does methylmercury-induced hypercholesterolemia play a causal role in its neurotoxicity and cardiovascular disease? Toxicol Sci 130:373-382. https://doi.org/10.1093/toxsci/kfs252
  16. Zhang Y, Xu C, Fu Z, Shu Y, Zhang J, Lu C, Mo X (2018) Associations between total mercury and methyl mercury exposure and cardiovascular risk factors in US adolescents. Environ Sci Pollut Res Int 25:6265-6272. https://doi.org/10.1007/s11356-017-0905-2
  17. Lusis AJ (2000) Atherosclerosis. Nature 407:233-241. https://doi.org/10.1038/35025203
  18. Salonen JT, Seppanen K, Nyyssonen K, Korpela H, Kauhanen J, Kantola M, Tuomilehto J, Esterbauer H, Tatzber F, Salonen R (1995) Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in Eastern Finnish men. Circulation 91:645-655. https://doi.org/10.1161/01.CIR.91.3.645
  19. Yoshizawa K, Rimm EB, Morris JS, Spate VL, Cheng HC, Spiegelman D, Stampfer MJ, Willett WC (2002) Mercury and the risk of coronary heart disease in men. N Engl J Med 347:1755-1760. https://doi.org/10.1056/NEJMoa021437
  20. Virtanen JK, Rissanen TH, Voutilainen S, Tuomainen TP (2007) Mercury as a risk factor for cardiovascular diseases. J Nutr Biochem 18:75-85. https://doi.org/10.1016/j.jnutbio.2006.05.001
  21. Breslow JL (1996) Mouse models of atherosclerosis. Science 272:685-688. https://doi.org/10.1126/science.272.5262.685
  22. Teupser D, Persky AD, Breslow JL (2003) Induction of atherosclerosis by low-fat, semisynthetic diets in LDL receptor-deficient C57BL/6J and FVB/NJ mice: Comparison of lesions of the aortic root, brachiocephalic artery, and whole aorta (en face measurement). Arterioscler Thromb Vasc Biol 23:1907-1913. https://doi.org/10.1161/01.ATV.0000090126.34881.B1
  23. Centa M, Ketelhuth DFJ, Malin S, Gistera A (2019) Quantification of atherosclerosis in mice. J Vis Exp 148:e59828. https://doi.org/10.3791/59828
  24. Wouters K, Shiri-Sverdlov R, van Gorp PJ, van Bilsen M, Hofker MH (2005) Understanding hyperlipidemia and atherosclerosis: Lessons from genetically modified apoe and ldlr mice. Clin Chem Lab Med 43:470-479. https://doi.org/10.1515/CCLM.2005.085
  25. Veseli EB, Perrotta P, Meyer GRA, Roth L, Van der Donckt C, Martinet W, De Meyer GRY (2017) Animal models of atherosclerosis. Eur J Pharmacol 816:3-13. https://doi.org/10.1016/j.ejphar.2017.05.010
  26. Schionning JD, Eide R, Ernst E, Danscher G, Moller-Madsen B (1997) The effect of selenium on the localization of autometallographic mercury in dorsal root ganglia of rats. J Histochem 29:183-191. https://doi.org/10.1023/A:1026493607861
  27. Dietrich MO, Mantese CE, Dos AG, Souza DO, Farina M (2005) Motor impairment induced by oral exposure to methylmercury in adult mice. Environ Toxicol Pharmacol 19:169-175. https://doi.org/10.1016/j.etap.2004.07.004
  28. Kumar A, Lindner V (1997) Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow. Arterioscler Thromb Vasc Biol 17:2238-2244. https://doi.org/10.1161/01.ATV.17.10.2238
  29. Guyton JR, Hartley CJ (1985) Flow restriction of one carotid artery in juvenile rats inhibits growth of arterial diameter. Am J Physiol Heart Circ Physiol 17:540-546. https://doi.org/10.1152/ajpheart.1985.248.4.h540
  30. Langille BL, Bendeck MP, Keeley FW (1989) Adaptations of carotid arteries of young and mature rabbits to reduced carotid blood flow. Am J Physiol Heart Circ Physiol 256:931-939. https://doi.org/10.1152/ajpheart.1989.256.4.h931
  31. Nam D, Ni CW, Rezvan A, Suo J, Budzyn K, Llanos A, Harrison DG, Giddens DP, Jo H (2010) A model of disturbed flow-induced atherosclerosis in mouse carotid artery by partial ligation and a simple method of rna isolation from carotid endothelium. J Vis Exp 40:e1861. https://doi.org/10.3791/1861
  32. Lagrange J, Kossmann S, Kiouptsi K, Wenzel P (2018) Visualizing leukocyte rolling and adhesion in angiotensin II-infused mice: techniques and pitfalls. J Vis Exp 131:e56948. https://doi.org/10.3791/56948
  33. Fox AJ (1993) How to measure carotid stenosis. Radiology 186:316-318. https://doi.org/10.1148/radiology.186.2.8421726
  34. Crespo-Lopez ME, Herculano AM, Corvelo TC, Do Nascimento JL (2005) Mercury and neurotoxicity. Nat Rev Neurol 40:441-447. https://doi.org/10.33588/rn.4007.2004499
  35. World Health Organization (2016) Guidance for identifying populations at risk from mercury exposure. WHO Publishing Food Safety. https://www.who.int/foodsafety/publications/risk-mercury-exposure/en/. Accessed 06 July 2020
  36. Castro NSS, Lima MDO (2018) Hair as a biomarker of long term mercury exposure in brazilian amazon: a systematic review. Int J Environ Res Public Health 15:500. https://doi.org/10.3390/ijerph15030500
  37. Arrifano GPF, Martin-Doimeadios RCR, Jimenez-Moreno M, Ramirez-Mateos V, da Silva NFS, Souza-Monteiro JR, Augusto-Oliveira M, Paraense RSO, Macchi BM, do NascimentoCrespo-Lopez JLMME (2018) Large-scale projects in the amazon and human exposure to mercury: the case-study of the Tucurui Dam. Ecotox Environ Safe 147:299-305. https://doi.org/10.1016/j.ecoenv.2017.08.048
  38. Arrifano GPF, Martin-Doimeadios RCR, Jimenez-Moreno M, Fernandez-Trujillo S, Augusto-Oliveira M, Souza-Monteiro JR, Macchi BM, Alvarez-Leite JI, Nascimento JLM, Amador MT, Santos S, Ribeiro-Dos-Santos A, Silva-Pereira LC, Oria RB, Crespo-Lopez ME (2018) Genetic susceptibility to neurodegeneration in amazon: apolipoprotein E genotyping in vulnerable populations exposed to mercury. Front Genet 9:285. https://doi.org/10.3389/fgene.2018.00285
  39. Arrifano GPF, Martin-Doimeadios RCR, Jimenez-Moreno M, Augusto-Oliveira M, Souza-Monteiro JR, Paraense RSO, Machado CR, Farina M, Macchi B, Nascimento JLM, Crespo-Lopez ME (2018) Assessing mercury intoxication in isolated/remote populations: Increased S100B mRNA in blood in exposed riverine inhabitants of the Amazon. Neurotoxicology 68:151-158. https://doi.org/10.1016/j.neuro.2018.07.018
  40. Cox C, Clarkson TW, Marsh DO, Amin-Zaki L, Tikriti S, Myers GG (1989) Dose-response analysis of infants prenatally exposed to methyl mercury: an application of a single compartment model to single-strand hair analysis. Environ Res 49:318-332. https://doi.org/10.1016/S0013-9351(89)80075-1
  41. Clarkson TW, Magos L, Myers GJ (2003) The toxicology of mercury-current exposures and clinical manifestations. N Engl J Med 349:1731-1737. https://doi.org/10.1056/NEJMra022471
  42. Park SK, Lee S, Basu N, Franzblau A (2013) Associations of blood and urinary mercury with hypertension in U.S. Adults: the NHANES 2003-2006. Environ Res 123:25-32. https://doi.org/10.1016/j.envres.2013.02.003
  43. Wildemann TM, Mirhosseini N, Siciliano SD, Weber LP (2015) Cardiovascular responses to lead are biphasic, while methylmercury, but not inorganic mercury, monotonically increases blood pressure in rats. Toxicology 328:1-11. https://doi.org/10.1016/j.tox.2014.11.009
  44. Houston MC (2011) Role of mercury toxicity in hypertension, cardiovascular disease, and stroke. J Clin Hypertens 13:621-627. https://doi.org/10.1111/j.1751-7176.2011.00489.x
  45. Ghizoni H, de Souza V, Straliotto MR, de Bem AF, Farina M, Hort MA (2017) Superoxide anion generation and oxidative stress in methylmercury-induced endothelial toxicity in vitro. Toxicol In Vitro 38:19-26. https://doi.org/10.1016/j.tiv.2016.10.010
  46. Arrifano GPF, Oliveira MA, Souza-Monteiro JR, Paraense RSO, Ribeiro-Dos-Santos A, Santos JRV, Silva ALC, Filho MS, Macchi BM, Nascimento JLM, Burbano RMR, Crespo-Lopez ME (2018) Role for apolipoprotein E in neurodegeneration and mercury intoxication. Front Biosci 10:229-241. https://doi.org/10.2741/e819
  47. Bittencourt LO, Dionizio A, Nascimento PC, Puty B, Leao 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 11:390-403. https://doi.org/10.1039/c8mt00297e
  48. Nogara PA, Oliveira CS, Schmitz GL, Piquini PC, Farina M, Aschner M, Rocha JBT (2019) Methylmercury's chemistry: from the environment to the mammalian brain. Biochim Biophys Acta Gen Subj 1863:129284. https://doi.org/10.1016/j.bbagen.2019.01.006
  49. Stachowicz A, Wisniewska A, Kus K, Kiepura A, Gebska A, Gajda M, Bialas M, Toton-Zuranska J, Stachyra K, Suski M, Jawien J, Korbut R, Olszanecki R (2019) The influence of trehalose on atherosclerosis and hepatic steatosis in apolipoprotein E knockout Mice. Int J Mol Sci 20:1552. https://doi.org/10.3390/ijms20071552
  50. Rutledge AC, Su Q, Adeli K (2010) Apolipoprotein B100 biogenesis: a complex array of intracellular mechanisms regulating folding, stability, and lipoprotein assembly. Biochem Cell Biol 88:251-267. https://doi.org/10.1139/O09-168
  51. Janssen CIF, Jansen D, Mutsaers MPC, Dederen PJWC, Geenen B, Mulder MT, Kiliaan Kiliaan AJ (2016) The effect of a high-fat diet on brain plasticity, inflammation and cognition in female ApoE4-knockin and ApoE-knockout mice. PLoS ONE 11:e0155307. https://doi.org/10.1371/journal.pone.0155307
  52. Lohmann C, Schafer N, Lukowicz TV, Stein MAS, Boren J, Rutti S, Wahli W, Donath MY, Luscher TF, Matter CM (2009) Atherosclerotic mice exhibit systemic inflammation in periadventitial and visceral adipose tissue, liver, and pancreatic islets. Atherosclerosis 207:360-367. https://doi.org/10.1016/j.atherosclerosis.2009.05.004
  53. Jin X, Hidiroglou N, Lok E, Taylor M, Kapal K, Ross N, Sarafin K, Lau A, De Souza A, Chan HM, Mehta R (2012) Dietary selenium (Se) and Vitamin E (VE) supplementation modulated methylmercury-mediated changes in markers of cardiovascular diseases in rats. Cardiovasc Toxicol 12:10-24. https://doi.org/10.1007/s12012-011-9134-y
  54. Fitch MN, Phillippi D, Zhang Y, Lucero J, Pandey RS, Liu J, Brower J, Allen MS, Campen MJ, McDonald JD, Lund AK (2019) Effects of inhaled air pollution on markers of integrity, inflammation, and microbiota profiles of the intestines in Apolipoprotein E knockout mice. Environ Res 181:108913. https://doi.org/10.1016/j.envres.2019.108913
  55. Getz GS, Reardon CA (2006) Diet and murine atherosclerosis. Arterioscler Thromb Vasc Biol 26:242-249. https://doi.org/10.1161/01.ATV.0000201071.49029.17
  56. Fazio S, Babaev VR, Murray AB, Hasty AH, Carter KJ, Gleaves LA, Atkinson JB, Linton MF (1997) Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. Proc Natl Acad Sci USA 94:4647-4652. https://doi.org/10.1073/pnas.94.9.4647