Toxicity interactions between manganese (Mn) and lead (Pb) or cadmium (Cd) in a model organism the nematode C. elegans

  • Cailing Lu
  • Kurt R. Svoboda
  • Kade A. Lenz
  • Claire Pattison
  • Hongbo Ma
Research Article

Abstract

Manganese (Mn) is considered as an emerging metal contaminant in the environment. However, its potential interactions with companying toxic metals and the associated mixture effects are largely unknown. Here, we investigated the toxicity interactions between Mn and two commonly seen co-occurring toxic metals, Pb and Cd, in a model organism the nematode Caenorhabditis elegans. The acute lethal toxicity of mixtures of Mn+Pb and Mn+Cd were first assessed using a toxic unit model. Multiple toxicity endpoints including reproduction, lifespan, stress response, and neurotoxicity were then examined to evaluate the mixture effects at sublethal concentrations. Stress response was assessed using a daf-16::GFP transgenic strain that expresses GFP under the control of DAF-16 promotor. Neurotoxicity was assessed using a dat-1::GFP transgenic strain that expresses GFP in dopaminergic neurons. The mixture of Mn+Pb induced a more-than-additive (synergistic) lethal toxicity in the worm whereas the mixture of Mn+Cd induced a less-than-additive (antagonistic) toxicity. Mixture effects on sublethal toxicity showed more complex patterns and were dependent on the toxicity endpoints as well as the modes of toxic action of the metals. The mixture of Mn+Pb induced additive effects on both reproduction and lifespan, whereas the mixture of Mn+Cd induced additive effects on lifespan but not reproduction. Both mixtures seemed to induce additive effects on stress response and neurotoxicity, although a quantitative assessment was not possible due to the single concentrations used in mixture tests. Our findings demonstrate the complexity of metal interactions and the associated mixture effects. Assessment of metal mixture toxicity should take into consideration the unique property of individual metals, their potential toxicity mechanisms, and the toxicity endpoints examined.

Keywords

Manganese Cadmium Lead Toxicity interaction Metal mixture C. elegans 

Notes

Acknowledgements

This work was conducted when C. Lu held a visiting scholar position at the University of Wisconsin-Milwaukee through the support of the Education Department of Guangxi Zhuang Autonomous Region, People’s Republic of China. The work was supported by the University of Wisconsin-Milwaukee through a start-up fund awarded to H. Ma.

References

  1. Ahmadi FA, Grammatopoulos TN, Poczobutt AM, Jones SM, Snell LD, Das M (2008) Dopamine selectively sensitizes dopaminergic neurons to rotenone-induced apoptosis. Neurochem Res 33:886–901CrossRefGoogle Scholar
  2. Aschner M, Guilarte TR, Schneider JS, Zheng W (2007) Manganese: recent advances in understanding its transport and neurotoxicity. Toxicol Appl Pharmacol 221:131–147CrossRefGoogle Scholar
  3. Aschner M, Chen P, Martinez-Finley EJ, Bornhorst J, Chakraborty S (2013) Metal-induced neurodegeneration in C. elegans. Front Aging Neurosci 5Google Scholar
  4. Baird DJ, Barber I, Bradley M, Soares AMVM, Calow P (1991) A comparative study of genotype sensitivity to acute toxic stress using clones of Daphnia magna Straus. Ecotoxicol Environ Saf 21(3):257–265CrossRefGoogle Scholar
  5. Baumeister R, Schaffitzel E, Hertweck M (2006) Endocrine signaling in Caenorhabditis elegans controls stress response and longevity. J Endocrinol 190:191–202CrossRefGoogle Scholar
  6. Benedetto A, Au C, Avila DS, Milatovic D, Aschner M (2010) Extracellular dopamine potentiates Mn-induced oxidative stress, lifespan reduction, and dopaminergic neurodegeneration in a BLI-3-dependent manner in Caenorhabditis elegans. PLoS Genet 6:e1001084CrossRefGoogle Scholar
  7. Bouchard M, Laforest F, Vandelac L, Bellinger D, Mergler D (2007) Hair manganese and hyperactive behaviors: pilot study of school-age children exposed through tap water. Environ Health Perspect 115:122–127CrossRefGoogle Scholar
  8. Broderius SJ (1990) Modeling the joint toxicity of xenobiotics to aquatic organisms: basic concepts and approaches. In: Mayes MA, Barron MG (eds) Aquatic toxicology and risk assessment, Vol. 14. STP 1124. American Society for TESTING AND materials, Philadephia, PA, pp 107–127Google Scholar
  9. Burton NC, Guilarte TR (2009) Manganese neurotoxicity: lessons learned from longitudinal studies in nonhuman primates. Environ Health Perspect 117:325–332CrossRefGoogle Scholar
  10. Cedergreen N (2014) Quantifying synergy: a systematic review of mixture toxicity studies within environmental toxicology. PLoS One 9(5):e96580CrossRefGoogle Scholar
  11. Cersosimo MG, Koller WC (2006) The diagnosis of manganese-induced parkinsonism. Neurotoxicology 27:340–346CrossRefGoogle Scholar
  12. Chen P, DeWitt MR, Bornhorst J, Soares FA, Mukhopadhyay S, Bowman AB (2015) Age- and manganese-dependent modulation of dopaminergic phenotypes in a C. elegans DJ-1 genetic model of Parkinson’s disease. Metallomics 7:289–298CrossRefGoogle Scholar
  13. Cooper NL, Joseph RB, Kumar A (2009) Toxicity of copper, lead, and zinc mixtures to Ceriodaphnia dubia and Daphnia carinata. Ecotoxicol Environ Saf 72(5):1523–1528CrossRefGoogle Scholar
  14. Cuypers A, Plusquin M, Remans T, Jozefczak M, Keunen E, Gielen H, Opdenakker K, Nair AR, Munters E, Artois TJ, Nawrot T, Vangronsveld J, Smeets K (2010) Cadmium stress: an oxidative challenge. Biometals 23(5):927–940.  https://doi.org/10.1007/s10534-010-9329-x CrossRefGoogle Scholar
  15. Davies PH, Brinkman SF (1994) Acute and chronic toxicity of manganese to exposed and unexposed rainbow and brown trout. Fort Collins, CO, Colorado Division of Wildlife (Federal Aid Project #F-243R-1) [cited in Reimer, 1999]Google Scholar
  16. Flora G, Deepesh G, Tiwari AR (2012) Toxicity of lead: a review with recent updates. InterdiscipToxicol 5(2):47–58 PMC. Web 22 June 2017Google Scholar
  17. Gao G, Wu Y, Guo Y (2003) Survey on chronic occupational hazards in welders. Chin J Ind Med:107–108Google Scholar
  18. Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M (2003) Dmt1: a mammalian transporter for multiple metals. Biometals 16:41–54CrossRefGoogle Scholar
  19. Gunter TE, Gavin CE, Aschner M, Gunter KK (2006) Speciation of manganese in cells and mitochondria: a search for the proximal cause of manganese neurotoxicity. Neurotoxicology 27:765–776CrossRefGoogle Scholar
  20. Hall J, Haas KL, Freedman JH (2012) Role of MTL-1, MTL-2, and CDR-1 in mediating cadmium sensitivity in Caenorhabditis elegans. Toxicol Sci 128(2):418–426CrossRefGoogle Scholar
  21. Harford AJ, Mooney TJ, Trenfield MA, van Dam RA (2015) Manganese toxicity to tropical freshwater species in low hardness water. Environ Toxicol Chem 34(12):2856–2863CrossRefGoogle Scholar
  22. Ingersoll RT, Montgomery EB, Aposhian HV (1999) Central nervous system toxicity of manganese. II: cocaine or reserpine inhibit manganese concentration in the rat brain. Neurotoxicology 20:467–476Google Scholar
  23. International Manganese Institute (2009) The chronic toxicity of manganese to the amphipod crustacean Hyalella Azteca using a standardized flow-through experiment. Albany, Oregon, USAGoogle Scholar
  24. Jonker MJ, Svendsen C, Bedaux JJM, Bongers M, Kammenga JE (2005) Significance testing of synergistic/antagonistic, dose level-dependent, or dose ratio-dependent effects in mixture dose-response analysis. Environ Toxicol Chem 24(10):2701–2713CrossRefGoogle Scholar
  25. Kern CH, Smith DR (2011) Preweaning mn exposure leads to prolonged astrocyte activation and lasting effects on the dopaminergic system in adult male rats. Synapse 65:532–544CrossRefGoogle Scholar
  26. Khan K, Factor-Litvak P, Wasserman GA, Liu X, Ahmed E, Parvez F (2011) Manganese exposure from drinking water and children's classroom behavior in Bangladesh. Environ Health Perspect 119:1501–1506CrossRefGoogle Scholar
  27. Kraak MHS, Lavy D, Schoon H, Toussaint M, Peeters WHM, van Straalen NM (1994) Ecotoxicity of mixtures of metals to the zebra mussel Dreissena polymorpha. Environ Toxicol Chem 13(1):109–114CrossRefGoogle Scholar
  28. Leung MC, Williams PL, Benedetto A, Au C, Helmcke KJ, Aschner M, Meyer JN (2008) Caenorhabditis elegans: an emerging model in biomedical and environmental toxicology. Toxicol Sci 106(1):5–28CrossRefGoogle Scholar
  29. Li MS, Yang SX (2008) Heavy metal contamination in soils and phytoaccumulation in a manganese mine wasteland, South China. Air Soil Water Res 1:31–41CrossRefGoogle Scholar
  30. Liang Y, Xiang Q (2004) Occupational health services in PR China. Toxicology 198:45–54CrossRefGoogle Scholar
  31. Ma H, Glenn TC, Jagoe CH, Jones KL, Williams PL (2009) A transgenic strain of the nematode C. elegans as a biomonitor for heavy metal contamination. Environ Toxicol Chem 28(6):1311–1318CrossRefGoogle Scholar
  32. Marking LL (1985) Toxicity of chemical mixtures. In: Rand GM, Petrocellim SR (eds) Fundamentals of aquatic toxicology: methods and applications. Hemisphere, New York, pp 164–176Google Scholar
  33. Milatovic D, Zaja-Milatovic S, Gupta RC, Yu Y, Aschner M (2009) Oxidative damage and neurodegeneration in manganese-induced neurotoxicity. Toxicol Appl Pharmacol 240:219–225CrossRefGoogle Scholar
  34. Neal AP, Guilarte TR (2013) Mechanisms of lead and manganese neurotoxicity. Toxicol Res 2:99–114CrossRefGoogle Scholar
  35. O’Neal and Zheng (2015) Manganese toxicity upon overexposure: a decade in review. Curr Environ Health Rep 2(3):315–328CrossRefGoogle Scholar
  36. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA (1997) The fork head transcription factor daf-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389:994–999CrossRefGoogle Scholar
  37. Paris I, Segura-Aguilar J (2011) The role of metal ions in dopaminergic neuron degeneration in parkinsonism and parkinson’s disease. Monatshefte für Chemie -Chemical Monthly 142:365–374CrossRefGoogle Scholar
  38. Pinsino A, Matranga V, Carmela Roccheri M (2012) Manganese: a new emerging contaminant in the environment. In: Srivastava JK (ed) Environmental Contamination, pp 17–35 ISBN 978-953-51-0120-8Google Scholar
  39. Pluskota A, Horzowski E, Bossinger O, Mikecz A (2009) In Caenorhabditis elegans Nanoparticle-Bio-Interactions Become Transparent: Silica-Nanoparticles Induce Reproductive Senescence. PLoS One 4(8):e6622Google Scholar
  40. Posthuma L, Baerselman R, Van Veen RP, Dirven-Van BEM (1997) Single and joint toxic effects of copper and zinc on reproduction of Enchytraeus crypticusin relation to sorption of metals in soils. Ecotoxicol Environ Saf 38(2):108–121CrossRefGoogle Scholar
  41. Rai A, Maurya SK, Khare P, Srivastava A, Bandyopadhyay S (2010) Characterization of developmental neurotoxicity of As, Cd, and Pb mixture: synergistic action of metal mixture in glial and neuronal functions. Toxicol Sci 118:586–601CrossRefGoogle Scholar
  42. Roh JY, Lee J, Choi J (2006) Assessment of stress-related gene expression in the heavy metal-exposed nematode Caenorhabditis elegans: a potential biomarker for metal-induced toxicity monitoring and environmental risk assessment. Environ Toxicol Chem 25:2946–2956CrossRefGoogle Scholar
  43. Sawin ER, Ranganathan R, Horvitz HR (2000) C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron 26(3):619–631CrossRefGoogle Scholar
  44. Settivari R, Levora J, Nass R (2009) The divalent metal transporter homologues SMF-1/2 mediate dopamine neuron sensitivity in caenorhabditis elegans models of manganism and Parkinson disease. J Biol Chem 284:35758–35768CrossRefGoogle Scholar
  45. Settivari R, VanDuyn N, LeVora J, Nass R (2013) The Nrf2/SKN-1-dependent glutathione S-transferase pi homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of manganism. Neurotoxicology 38:51–60CrossRefGoogle Scholar
  46. Stiernagle T (2006) Maintenance of C. elegans. WormBook, ed. The C. elegans research community, WormBook,  https://doi.org/10.1895/wormbook.1.101.1, http://www.wormbook.org
  47. Sunda WG, Huntsman SA (1998a) Control of Cd concentrations in a coastal diatom by interactions among free ionic Cd, Zn, and Mn in seawater. Environ Sci Technol 32:2961–2968CrossRefGoogle Scholar
  48. Sunda WG, Huntsman SA (1998b) Interactive effects of external manganese, the toxic metals copper and zinc, and light in controlling cellular manganese and growth in a coastal diatom. Limnol Oceanogr 43:1467–1475CrossRefGoogle Scholar
  49. Thompson J, Bannigan J (2008) Cadmium: toxic effects on the reproductive system and the embryo. Reprod Toxicol 25:304–315CrossRefGoogle Scholar
  50. Times GRH (2003) Personal injury litigation against welding rod manufacturers. GeneralCologne Re Hazardous Times 1–5Google Scholar
  51. Utgikar VP, Chaudhary N, Koeniger A, Tabak HH, Haines JR, Govind R (2004) Toxicity of metals and metal mixtures: analysis of concentration and time dependence for zinc and copper. Water Res 38(17):3651–3658CrossRefGoogle Scholar
  52. Van Gestel CAM, Paul JH (1997) Interaction of Cd and Zn toxicity for Folsomia candida Willem (Collembola: Isotomidae) in relation to bioavailability in soil. Environ Toxicol Chem 16(6):1177–1186CrossRefGoogle Scholar
  53. Verity MA (1995) Nervous system. In: Goyer RA, Klaassen CD, Waalkes MP (eds) Metal toxicology. Academic Press, San Diego, pp 199–226CrossRefGoogle Scholar
  54. Vijver MG, Elliott EG, Peijenbury WJ, de Snoo GR (2011) Response predictions for organisms water-exposed to metal mixtures: a meta-analysis. Environ Toxicol Chem 30(6):1482–1487CrossRefGoogle Scholar
  55. Wah Chu K, Chow KL (2002) Synergistic toxicity of multiple heavy metals is revealed by a biological assay using a nematode and its transgenic derivative. Aquat Toxicol 61:53–64CrossRefGoogle Scholar
  56. Wang X (2003) 1160 welders’ health condition analysis. Occup Health 19:9–10 [in Chinese]Google Scholar
  57. Wang B, Du Y (2013) Cadmium and its neurotoxic effects. Oxidative medicine and cellular longevity. Volume 2013. Article ID 898034Google Scholar
  58. Weltje L (1998) Mixture toxicity and tissue interactions of Cd, Cu, Pb and Zn in earthworms (Oligochaeta) in laboratory and field soils: a critical evaluation of data. Chemosphere 36(12):2643–2660CrossRefGoogle Scholar
  59. Williams PL, Dusenbery DB (1990) Aquatic toxicity testing using the nematode, Caenorhabditis elegans. Environ Toxicol Chem 9:1285–1290CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Joseph J. Zilber School of Public HealthUniversity of Wisconsin-MilwaukeeMilwaukeeUSA
  2. 2.School of Public HealthGuangxi Medical UniversityNanningChina

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