Skip to main content

Advertisement

Log in

Methylmercury Intoxication Promotes Metallothionein Response and Cell Damage in Salivary Glands of Rats

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

Abstract

Environmental and occupational mercury exposure is considered a major public health issue. Despite being well known that MeHg exposure causes adverse effects in several physiologic functions, MeHg effects on salivary glands still not completely elucidated. Here, we investigated the cellular MeHg-induced damage in the three major salivary glands (parotid, submandibular, and sublingual) of adult rats after chronic, systemic and low doses of MeHg exposure. Rats were exposed by 0.04 mg/kg/day over 60 days. After that, animals were euthanized and all three glands were collected. We evaluated total Hg accumulation, metallothionein I/II (MT I/II), α-smooth muscle actin (α-SMA), and cytokeratin 18 (CK18) immune expression. Our results have showed that MeHg is able to disrupt gland tissue and to induce a protective mechanism by MT I/II expression. We also showed that cell MT production is not enough to protect gland tissue against cellular structural damage seen by reducing marking of cytoskeletal proteins as CK18 and α-SMA. Our data suggest that chronic MeHg exposure in low-daily doses is able to induce cellular damage in rat salivary glands.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Clarkson TW, Magos L (2006) The toxicology of mercury and its chemical compounds. Crit Rev Toxicol 36(8):609–662. https://doi.org/10.1080/10408440600845619

    Article  CAS  PubMed  Google Scholar 

  2. Li WC, Tse HF (2015) Health risk and significance of mercury in the environment. Environ Sci Pollut Res Int 22(1):192–201. https://doi.org/10.1007/s11356-014-3544-x

    Article  CAS  PubMed  Google Scholar 

  3. Bernhoft RA (2012) Mercury toxicity and treatment: a review of the literature. J Environ Public Health 2012:460508. https://doi.org/10.1155/2012/460508

    Article  PubMed  Google Scholar 

  4. Kim SJ, Lee HK, Badejo AC, Lee WC, Moon HB (2016) Species-specific accumulation of methyl and total mercury in sharks from offshore and coastal waters of Korea. Mar Pollut Bull 102(1):210–215. https://doi.org/10.1016/j.marpolbul.2015.11.038

    Article  CAS  PubMed  Google Scholar 

  5. Li SJ, Zhang SH, Chen HP, Zeng CH, Zheng CX, Li LS, Liu ZH (2010) Mercury-induced membranous nephropathy: clinical and pathological features. Clin J Am Soc Nephrol: CJASN 5(3):439–444. https://doi.org/10.2215/CJN.07571009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tan SW, Meiller JC, Mahaffey KR (2009) The endocrine effects of mercury in humans and wildlife. Crit Rev Toxicol 39(3):228–269. https://doi.org/10.1080/10408440802233259

    Article  CAS  PubMed  Google Scholar 

  7. Holmes P, James KA, Levy LS (2009) Is low-level environmental mercury exposure of concern to human health? Sci Total Environ 408(2):171–182. https://doi.org/10.1016/j.scitotenv.2009.09.043

    Article  CAS  PubMed  Google Scholar 

  8. Bittencourt LO, Puty B, Charone S, WAB A, Farias-Junior PM, MCF S, Crespo-Lopez ME, AdL L, MAR B, Lima RR (2017) Oxidative Biochemistry Disbalance and Changes on Proteomic Profile in Salivary Glands of Rats Induced by Chronic Exposure to Methylmercury. Oxidative Med Cell Longev 2017:15. https://doi.org/10.1155/2017/5653291

    Article  CAS  Google Scholar 

  9. Islas-Granillo H, Borges-Yanez A, Fernandez-Barrera MA, Avila-Burgos L, Patino-Marin N, Marquez-Corona ML, Mendoza-Rodriguez M, Medina-Solis CE (2017) Relationship of hyposalivation and xerostomia in Mexican elderly with socioeconomic, sociodemographic and dental factors. Sci Rep 7:40686. https://doi.org/10.1038/srep40686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mese H, Matsuo R (2007) Salivary secretion, taste and hyposalivation. J Oral Rehabil 34(10):711–723. https://doi.org/10.1111/j.1365-2842.2007.01794.x

    Article  CAS  PubMed  Google Scholar 

  11. Kong HK, Wong MH, Chan HM, Lo SC (2013) Chronic exposure of adult rats to low doses of methylmercury induced a state of metabolic deficit in the somatosensory cortex. J Proteome Res 12(11):5233–5245. https://doi.org/10.1021/pr400356v

    Article  CAS  PubMed  Google Scholar 

  12. Akagi H, Nishimura H (1991) Speciation of Mercury in the Environment. In: Suzuki T, Imura N, Clarkson TW (eds) Advances in Mercury Toxicology. Springer US, Boston, pp 53–76. https://doi.org/10.1007/978-1-4757-9071-9_3

    Chapter  Google Scholar 

  13. Teixeira FB, Fernandes RM, Farias-Junior PM, Costa NM, Fernandes LM, Santana LN, Silva-Junior AF, Silva MC, Maia CS, Lima RR (2014) Evaluation of the effects of chronic intoxication with inorganic mercury on memory and motor control in rats. Int J Environ Res Public Health 11(9):9171–9185. https://doi.org/10.3390/ijerph110909171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bhandari S, Melchiorre C, Dostie K, Laukens D, Devisscher L, Louwrier A, Thees A, Lynes MA (2017) Detection and Manipulation of the Stress Response Protein Metallothionein. Curr Protoc Toxicol 71:17.19.11–17.19.28. https://doi.org/10.1002/cptx.17

    Article  CAS  Google Scholar 

  15. Chu PG, Weiss LM (2002) Keratin expression in human tissues and neoplasms. Histopathology 40(5):403–439

    Article  CAS  PubMed  Google Scholar 

  16. Ogawa Y (2003) Immunocytochemistry of myoepithelial cells in the salivary glands. Prog Histochem Cytochem 38(4):343–426

    Article  CAS  PubMed  Google Scholar 

  17. da Costa NM, Correa RS, Junior IS, Figueiredo AJ, Vilhena KF, Farias-Junior PM, Teixeira FB, Ferreira NM, Pereira-Junior JB, Dantas K, da Silva MC, Silva-Junior AF, Alves-Junior Sde M, Pinheiro Jde J, Lima RR (2014) Physical, chemical, and immunohistochemical investigation of the damage to salivary glands in a model of intoxication with aluminium citrate. Int J Environ Res Public Health 11(12):12429–12440. https://doi.org/10.3390/ijerph111212429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Silva AF, Aguiar MS, Carvalho OS, Santana Lde N, Franco EC, Lima RR, Siqueira NV, Feio RA, Faro LR, Gomes-Leal W (2013) Hippocampal neuronal loss, decreased GFAP immunoreactivity and cognitive impairment following experimental intoxication of rats with aluminum citrate. Brain Res 1491:23–33. https://doi.org/10.1016/j.brainres.2012.10.063

    Article  CAS  PubMed  Google Scholar 

  19. Clarkson TW (1972) The biological properties and distribution of mercury. Biochem J 130(2):61P–63P

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu J, Lu YF, Li WK, Zhou ZP, Li YY, Yang X, Li C, Du YZ, Wei LX (2016) Mercury sulfides are much less nephrotoxic than mercury chloride and methylmercury in mice. Toxicol Lett 262:153–160. https://doi.org/10.1016/j.toxlet.2016.10.003

    Article  CAS  PubMed  Google Scholar 

  21. Clarkson TW (2002) The three modern faces of mercury. Environ Health Perspect 110(Suppl 1):11–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shi JZ, Kang F, Wu Q, Lu YF, Liu J, Kang YJ (2011) Nephrotoxicity of mercuric chloride, methylmercury and cinnabar-containing Zhu-Sha-An-Shen-Wan in rats. Toxicol Lett 200(3):194–200. https://doi.org/10.1016/j.toxlet.2010.11.015

    Article  CAS  PubMed  Google Scholar 

  23. Schmid K, Sassen A, Staudenmaier R, Kroemer S, Reichl FX, Harreus U, Hagen R, Kleinsasser N (2007) Mercuric dichloride induces DNA damage in human salivary gland tissue cells and lymphocytes. Arch Toxicol 81(11):759–767. https://doi.org/10.1007/s00204-007-0208-3

    Article  CAS  PubMed  Google Scholar 

  24. Ikeda R (2011) Morphological and Histochemical Changes in the Parenchyma of the Rat Parotid and Sublingual Glands with Growth and Aging. J Oral Biosci 53(4):289–297. https://doi.org/10.1016/S1349-0079(11)80021-6

    Article  Google Scholar 

  25. Fedirko NV, Kruglikov IA, Kopach OV, Vats JA, Kostyuk PG, Voitenko NV (2006) Changes in functioning of rat submandibular salivary gland under streptozotocin-induced diabetes are associated with alterations of Ca2+ signaling and Ca2+ transporting pumps. Biochim Biophys Acta 1762(3):294–303. https://doi.org/10.1016/j.bbadis.2005.12.002

    Article  CAS  PubMed  Google Scholar 

  26. Yasutake A, Nakamura M (2011) Induction by mercury compounds of metallothioneins in mouse tissues: inorganic mercury accumulation is not a dominant factor for metallothionein induction in the liver. J Toxicol Sci 36(3):365–372

    Article  CAS  PubMed  Google Scholar 

  27. Dabrio M, Rodriguez AR, Bordin G, Bebianno MJ, De Ley M, Sestakova I, Vasak M, Nordberg M (2002) Recent developments in quantification methods for metallothionein. J Inorg Biochem 88(2):123–134

    Article  CAS  PubMed  Google Scholar 

  28. Chan J, Huang Z, Merrifield ME, Salgado MT, Stillman MJ (2002) Studies of metal binding reactions in metallothioneins by spectroscopic, molecular biology, and molecular modeling techniques. Coord Chem Rev 233(Supplement C):319–339. https://doi.org/10.1016/S0010-8545(02)00176-5

    Article  Google Scholar 

  29. Thirumoorthy N, Shyam Sunder A, Manisenthil Kumar K, Senthil Kumar M, Ganesh G, Chatterjee M (2011) A review of metallothionein isoforms and their role in pathophysiology. World J Surg Oncol 9:54. https://doi.org/10.1186/1477-7819-9-54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Higashimoto M, Isoyama N, Ishibashi S, Inoue M, Takiguchi M, Suzuki S, Ohnishi Y, Sato M (2009) Tissue-dependent preventive effect of metallothionein against DNA damage in dyslipidemic mice under repeated stresses of fasting or restraint. Life Sci 84(17-18):569–575. https://doi.org/10.1016/j.lfs.2009.01.022

    Article  CAS  PubMed  Google Scholar 

  31. Babula P, Masarik M, Adam V, Eckschlager T, Stiborova M, Trnkova L, Skutkova H, Provaznik I, Hubalek J, Kizek R (2012) Mammalian metallothioneins: properties and functions. Metallomics: Integr Biometal Sci 4(8):739–750. https://doi.org/10.1039/c2mt20081c

    Article  CAS  Google Scholar 

  32. Hwang TL, Chen HY, Changchien TT, Wang CC, Wu CM (2013) The cytotoxicity of mercury chloride to the keratinocytes is associated with metallothionein expression. Biomed Rep 1(3):379–382. https://doi.org/10.3892/br.2013.65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schurz F, Sabater-Vilar M, Fink-Gremmels J (2000) Mutagenicity of mercury chloride and mechanisms of cellular defence: the role of metal-binding proteins. Mutagenesis 15(6):525–530

    Article  CAS  PubMed  Google Scholar 

  34. Thier R, Bonacker D, Stoiber T, Bohm KJ, Wang M, Unger E, Bolt HM, Degen G (2003) Interaction of metal salts with cytoskeletal motor protein systems. Toxicol Lett 140-141:75–81

    Article  CAS  PubMed  Google Scholar 

  35. Nersesyan A, Kundi M, Waldherr M, Setayesh T, Misik M, Wultsch G, Filipic M, Mazzaron Barcelos GR, Knasmueller S (2016) Results of micronucleus assays with individuals who are occupationally and environmentally exposed to mercury, lead and cadmium. Mutat Res 770(Pt A):119–139. https://doi.org/10.1016/j.mrrev.2016.04.002

    Article  CAS  Google Scholar 

  36. Crespo-Lopez ME, Macedo GL, Pereira SI, Arrifano GP, Picanco-Diniz DL, do Nascimento JL, Herculano AM (2009) Mercury and human genotoxicity: critical considerations and possible molecular mechanisms. Pharmacol Res 60(4):212–220. https://doi.org/10.1016/j.phrs.2009.02.011

    Article  CAS  PubMed  Google Scholar 

  37. Coulombe PA, Omary MB (2002) ‘Hard’ and ‘soft’ principles defining the structure, function and regulation of keratin intermediate filaments. Curr Opin Cell Biol 14(1):110–122

    Article  CAS  PubMed  Google Scholar 

  38. Ma L, Xu J, Coulombe PA, Wirtz D (1999) Keratin Filament Suspensions Show Unique Micromechanical Properties. J Biol Chem 274(27):19145–19151. https://doi.org/10.1074/jbc.274.27.19145

    Article  CAS  PubMed  Google Scholar 

  39. Oriolo AS, Wald FA, Ramsauer VP, Salas PJ (2007) Intermediate filaments: a role in epithelial polarity. Exp Cell Res 313(10):2255–2264. https://doi.org/10.1016/j.yexcr.2007.02.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Moll R, Divo M, Langbein L (2008) The human keratins: biology and pathology. Histochem Cell Biol 129(6):705–733. https://doi.org/10.1007/s00418-008-0435-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Balachander N, Masthan KMK, , Anbazhagan V (2015) Myoepithelial cells in pathology. J Pharm Bioallied Sci 7 (Suppl 1):S190-S193. https://doi.org/10.4103/0975-7406.155898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Saleh J, Figueiredo MA, Cherubini K, Salum FG (2015) Salivary hypofunction: an update on aetiology, diagnosis and therapeutics. Arch Oral Biol 60(2):242–255. https://doi.org/10.1016/j.archoralbio.2014.10.004

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Brazilian National Council for Scientific and Technological Development (CNPq), Fundação de Amparo a Pesquisa do Estado do Pará (FAPESPA), and Pró-Reitoria de Pesquisa e Pós-Graduação da UFPA (PROPESP, UFPA, Brazil). Leidiane A. O. Lima is a scholar supported by UFPA. Rafael R. Lima is an investigator from CNPq (Edital MCTI/CNPQ/Universal 14/2014).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rafael Rodrigues Lima.

Ethics declarations

All procedures were previously approved by Ethics committee on animal experimentation by Federal University of Para (BIO 225-14 - CEPAE-UFPA) following the guidelines suggested by NIH Guide to Care and Use of Laboratory Animals.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lima, L.A.d.O., Bittencourt, L.O., Puty, B. et al. Methylmercury Intoxication Promotes Metallothionein Response and Cell Damage in Salivary Glands of Rats. Biol Trace Elem Res 185, 135–142 (2018). https://doi.org/10.1007/s12011-017-1230-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-017-1230-9

Keywords

Navigation