Neurotoxicity Research

, Volume 35, Issue 1, pp 208–216 | Cite as

Sex-Specific Response of Caenorhabditis elegans to Methylmercury Toxicity

  • Joanna A. RuszkiewiczEmail author
  • Gabriel Teixeira de Macedo
  • Antonio Miranda-Vizuete
  • Aaron B. Bowman
  • Julia Bornhorst
  • Tanja Schwerdtle
  • Felix A. Antunes Soares
  • Michael Aschner


Methylmercury (MeHg), an abundant environmental pollutant, has long been known to adversely affect neurodevelopment in both animals and humans. Several reports from epidemiological studies, as well as experimental data indicate sex-specific susceptibility to this neurotoxicant; however, the molecular bases of this process are still not clear. In the present study, we used Caenorhabditis elegans (C. elegans), to investigate sex differences in response to MeHg toxicity during development. Worms at different developmental stage (L1, L4, and adult) were treated with MeHg for 1 h. Lethality assays revealed that male worms exhibited significantly higher resistance to MeHg than hermaphrodites, when at L4 stage or adults. However, the number of worms with degenerated neurons was unaffected by MeHg, both in males and hermaphrodites. Lower susceptibility of males was not related to changes in mercury (Hg) accumulation, which was analogous for both wild-type (wt) and male-rich him-8 strain. Total glutathione (GSH) levels decreased upon MeHg in him-8, but not in wt. Moreover, the sex-dependent response of the cytoplasmic thioredoxin system was observed—males exhibited significantly higher expression of thioredoxin TRX-1, and thioredoxin reductase TRXR-1 expression was downregulated upon MeHg treatment only in hermaphrodites. These outcomes indicate that the redox status is an important contributor to sex-specific sensitivity to MeHg in C. elegans.


Methylmercury Sex Male C. elegans Antioxidant Thioredoxin 


Funding Information

This work has been supported by the National Institutes of Health [NIEHS R01ES07331 and R01ES10563; MA and ABB]. We thank the German Research Foundation (DFG) for the financial support of BO 4103/2-1 as well as the DFG Research Unit TraceAge (FOR 2558). C. elegans strains were provided by the Caenorhabditis Genetics Center (CGC, University of Minnesota, USA), which is funded by NIH Office of Research Infrastructure Programs. We would like to acknowledge Hillary Guzik for expert assistance in microscopy. The imaging was conducted in the Analytical Imaging Facility, which is funded by the NCI Cancer Grant P30CA013330.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.


  1. Antunes Dos Santos A, Appel Hort M, Culbreth M, Lopez-Granero C, Farina M, Rocha JB, Aschner M (2016) Methylmercury and brain development: a review of recent literature. J Trace Elem Med Biol 38:99–107CrossRefGoogle Scholar
  2. Avila D, Helmcke K, Aschner M (2012) The Caenorhabiditis elegans model as a reliable tool in neurotoxicology. Hum Exp Toxicol 31:236–243CrossRefGoogle Scholar
  3. Caito SW, Aschner M (2015) Quantification of glutathione in Caenorhabditis elegans. Curr Protoc Toxicol 64:6.18.1–6.18.6CrossRefGoogle Scholar
  4. Chen TY, Tsai KL, Lee TY, Chiueh CC, Lee WS, Hsu C (2010) Sex-specific role of thioredoxin in neuroprotection against iron-induced brain injury conferred by estradiol. Stroke 41:160–165CrossRefGoogle Scholar
  5. Edoff K, Raciti M, Moors M, Sundstrom E, Ceccatelli S (2017) Gestational age and sex influence the susceptibility of human neural progenitor cells to low levels of MeHg. Neurotox Res 32:683–693CrossRefGoogle Scholar
  6. Farina M, Aschner M (2017) Methylmercury-induced neurotoxicity: focus on pro-oxidative events and related consequences. Adv Neurobiol 18:267–286CrossRefGoogle Scholar
  7. Farina M, Rocha JB, Aschner M (2011) Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies. Life Sci 89:555–563CrossRefGoogle Scholar
  8. Fierro-Gonzalez JC, Cornils A, Alcedo J, Miranda-Vizuete A, Swoboda P (2011a) The thioredoxin TRX-1 modulates the function of the insulin-like neuropeptide DAF-28 during dauer formation in Caenorhabditis elegans. PLoS One 6:e16561CrossRefGoogle Scholar
  9. Fierro-Gonzalez JC, Gonzalez-Barrios M, Miranda-Vizuete A, Swoboda P (2011b) The thioredoxin TRX-1 regulates adult lifespan extension induced by dietary restriction in Caenorhabditis elegans. Biochem Biophys Res Commun 406:478–482CrossRefGoogle Scholar
  10. Goulet S, Dore FY, Mirault ME (2003) Neurobehavioral changes in mice chronically exposed to methylmercury during fetal and early postnatal development. Neurotoxicol Teratol 25:335–347CrossRefGoogle Scholar
  11. Grandjean P, Weihe P, White RF, Debes F (1998) Cognitive performance of children prenatally exposed to “safe” levels of methylmercury. Environ Res 77:165–172CrossRefGoogle Scholar
  12. Helmcke KJ, Aschner M (2010) Hormetic effect of methylmercury on Caenorhabditis elegans. Toxicol Appl Pharmacol 248:156–164CrossRefGoogle Scholar
  13. Helmcke KJ, Syversen T, Miller DM 3rd, Aschner M (2009) Characterization of the effects of methylmercury on Caenorhabditis elegans. Toxicol Appl Pharmacol 240:265–272CrossRefGoogle Scholar
  14. Hilbert ZA, Kim DH (2017) Sexually dimorphic control of gene expression in sensory neurons regulates decision-making behavior in C. elegans. Elife 6Google Scholar
  15. Hirayama K, Yasutake A, Inoue M (1987) Effect of sex hormones on the fate of methylmercury and on glutathione metabolism in mice. Biochem Pharmacol 36:1919–1924CrossRefGoogle Scholar
  16. Hodgkin J (1983) Male phenotypes and mating efficiency in CAENORHABDITIS ELEGANS. Genetics 103:43–64PubMedPubMedCentralGoogle Scholar
  17. Hodgkin J, Horvitz HR, Brenner S (1979) Nondisjunction mutants of the nematode CAENORHABDITIS ELEGANS. Genetics 91:67–94PubMedPubMedCentralGoogle Scholar
  18. Jee C, Vanoaica L, Lee J, Park BJ, Ahnn J (2005) Thioredoxin is related to life span regulation and oxidative stress response in Caenorhabditis elegans. Genes Cells 10:1203–1210CrossRefGoogle Scholar
  19. Johansson C, Castoldi AF, Onishchenko N, Manzo L, Vahter M, Ceccatelli S (2007) Neurobehavioural and molecular changes induced by methylmercury exposure during development. Neurotox Res 11:241–260CrossRefGoogle Scholar
  20. Leung YK, Ouyang B, Niu L, Xie C, Ying J, Medvedovic M, Chen A, Weihe P, Valvi D, Grandjean P, HO SM 2018. Identification of sex-specific DNA methylation changes driven by specific chemicals in cord blood in a Faroese birth cohort. Epigenetics 1–32Google Scholar
  21. Llop S, Lopez-Espinosa MJ, Rebagliato M, Ballester F (2013) Gender differences in the neurotoxicity of metals in children. Toxicology 311:3–12CrossRefGoogle Scholar
  22. Lohren H, Bornhorst J, Galla HJ, Schwerdtle T (2015) The blood-cerebrospinal fluid barrier--first evidence for an active transport of organic mercury compounds out of the brain. Metallomics 7:1420–1430CrossRefGoogle Scholar
  23. Marques RC, Bernardi JV, Abreu L, Dorea JG (2015) Neurodevelopment outcomes in children exposed to organic mercury from multiple sources in a tin-ore mine environment in Brazil. Arch Environ Contam Toxicol 68:432–441CrossRefGoogle Scholar
  24. Martinez-Finley EJ, Caito S, Slaughter JC, Aschner M (2013) The role of skn-1 in methylmercury-induced latent dopaminergic neurodegeneration. Neurochem Res 38:2650–2660CrossRefGoogle Scholar
  25. Mcelwee MK, Ho LA, Chou JW, Smith MV, Freedman JH (2013) Comparative toxicogenomic responses of mercuric and methyl-mercury. BMC Genomics 14:698CrossRefGoogle Scholar
  26. Miettinen JK, Rahola T, Hattula T, Rissanen K, Tillander M (1971) Elimination of 203Hg-methylmercury in man. Ann Clin Res 3:116–122PubMedGoogle Scholar
  27. Nguyen CQ, Hall DH, Yang Y, Fitch DH (1999) Morphogenesis of the Caenorhabditis elegans male tail tip. Dev Biol 207:86–106CrossRefGoogle Scholar
  28. Prpic I, Milardovic A, Vlasic-Cicvaric I, Spiric Z, Radic Nisevic J, Vukelic P, Snoj Tratnik J, Mazej D, Horvat M (2017) Prenatal exposure to low-level methylmercury alters the child’s fine motor skills at the age of 18 months. Environ Res 152:369–374CrossRefGoogle Scholar
  29. Rudgalvyte M, Peltonen J, Lakso M, Wong G (2017) Chronic MeHg exposure modifies the histone H3K4me3 epigenetic landscape in Caenorhabditis elegans. Comp Biochem Physiol C Toxicol Pharmacol 191:109–116CrossRefGoogle Scholar
  30. Ruszkiewicz JA, Bowman AB, Farina M, Rocha JBT, Aschner M (2016) Sex- and structure-specific differences in antioxidant responses to methylmercury during early development. Neurotoxicology 56:118–126CrossRefGoogle Scholar
  31. Ruszkiewicz JA, Pinkas A, Miah MR, Weitz RL, Lawes MJA, Akinyemi AJ, Ijomone OM, Aschner M (2018) C. elegans as a model in developmental neurotoxicology. Toxicol Appl PharmacolGoogle Scholar
  32. Saeed U, Karunakaran S, Meka DP, Koumar RC, Ramakrishnan S, Joshi SD, Nidadavolu P, Ravindranath V (2009) Redox activated MAP kinase death signaling cascade initiated by ASK1 is not activated in female mice following MPTP: novel mechanism of neuroprotection. Neurotox Res 16:116–126CrossRefGoogle Scholar
  33. Sagiv SK, Thurston SW, Bellinger DC, Amarasiriwardena C, Korrick SA (2012) Prenatal exposure to mercury and fish consumption during pregnancy and attention-deficit/hyperactivity disorder-related behavior in children. Arch Pediatr Adolesc Med 166:1123–1131CrossRefGoogle Scholar
  34. Thomas DJ, Fisher HL, Sumler MR, Marcus AH, Mushak P, Hall LL (1986) Sexual differences in the distribution and retention of organic and inorganic mercury in methyl mercury-treated rats. Environ Res 41:219–234CrossRefGoogle Scholar
  35. Weston HI, Sobolewski ME, Allen JL, Weston D, Conrad K, Pelkowski S, Watson GE, Zareba G, Cory-Slechta DA (2014) Sex-dependent and non-monotonic enhancement and unmasking of methylmercury neurotoxicity by prenatal stress. Neurotoxicology 41:123–140CrossRefGoogle Scholar
  36. Wyatt LH, Luz AL, Cao X, Maurer LL, Blawas AM, Aballay A, Pan WK, Meyer JN (2017) Effects of methyl and inorganic mercury exposure on genome homeostasis and mitochondrial function in Caenorhabditis elegans. DNA Repair (Amst) 52:31–48CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Joanna A. Ruszkiewicz
    • 1
    Email author
  • Gabriel Teixeira de Macedo
    • 2
  • Antonio Miranda-Vizuete
    • 3
  • Aaron B. Bowman
    • 4
  • Julia Bornhorst
    • 5
  • Tanja Schwerdtle
    • 5
  • Felix A. Antunes Soares
    • 2
  • Michael Aschner
    • 1
  1. 1.Department of Molecular PharmacologyAlbert Einstein College of Medicine BronxNew YorkUSA
  2. 2.Departamento de Bioquímica e Biologia MolecularUniversidade Federal de Santa MariaSanta MariaBrazil
  3. 3.Instituto de Biomedicina de SevillaHospital Universitario Virgen del Rocío/CSIC/Universidad de SevillaSevillaSpain
  4. 4.Department of PediatricsVanderbilt University Medical CenterNashvilleUSA
  5. 5.Department of Food Chemistry, Institute of Nutritional ScienceUniversity of PotsdamNuthetalGermany

Personalised recommendations