Skip to main content
Log in

Impact of chronic sub-lethal methylparaben exposure on cardiac hypoxia and alterations in neuroendocrine factors in zebrafish model

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Endocrine-disrupting chemicals have been shown to cause toxicity in different systems of the body including the endocrine, cardiovascular and nervous systems. This study aims to analyze the adverse effects of Methylparaben (MP) on cardiac functions, neurodevelopment, and behavior of zebrafish.

Methods and results

Adult male and female zebrafish were exposed to MP for 30 days to study the toxicity effects. Zebrafish were grouped into control, solvent control, 1/10th (110 ppb), 1/100th, and 1/1000th (1 ppb) lethal concentration 50 of MP. Neurobehavioral assays, acetylcholinesterase (AChE) activity, serotonin levels, and expression of genes—Hypoxia-inducible factor 1 alpha, Neurotrophic Receptor Tyrosine Kinase, Paired box protein Pax-6, and tnnt2 were investigated in zebrafish. Results of the study showed more anxiety-like behavior in MP-treated female zebrafish when compared to males on chronic exposure. There was a dose-dependent reduction of AChE activity in both male and female zebrafish. Female zebrafish showed a dose-dependent increase in serotonin level on MP exposure while male zebrafish showed a dose-independent decrease in serotonin level. On MP exposure, there was also a dose-dependent dysregulation in the expression of cardiac hypoxia and neuronal differentiation-related genes in female zebrafish while a dose-independent change was observed in male zebrafish.

Conclusion

Chronic MP exposure affects cardiac functions, neuronal functions, and behavior of zebrafish by exhibiting changes in AChE activity, serotonin levels, and altering the expression of genes related to cardiac hypoxia and neuronal differentiation even at sub-lethal doses.

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

Similar content being viewed by others

Data availability

Data and materials are available from the correspondence author upon request.

References

  1. Clotfelter ED, Bell AM, Levering KR (2004) The role of animal behaviour in the study of endocrine-disrupting chemicals. Anim Behav 68:665–676. https://doi.org/10.1016/j.anbehav.2004.05.004

    Article  Google Scholar 

  2. Nguyen VH, Phan Thi LA, Chandana PS et al (2021) The degradation of paraben preservatives: recent progress and sustainable approaches toward photocatalysis. Chemosphere 276:130163. https://doi.org/10.1016/j.chemosphere.2021.130163

    Article  CAS  PubMed  Google Scholar 

  3. Luzeena Raja G, Divya Subhashree K, Lite C et al (2019) Transient exposure of methylparaben to zebrafish (Danio rerio) embryos altered cortisol level, acetylcholinesterase activity and induced anxiety-like behaviour. Gen Comp Endocrinol 279:53–59. https://doi.org/10.1016/j.ygcen.2018.11.001

    Article  CAS  PubMed  Google Scholar 

  4. Sharan P (2010) An overview of Indian research in personality disorders. Indian J Psychiatry 52:250. https://doi.org/10.4103/0019-5545.69241

    Article  Google Scholar 

  5. Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902. https://doi.org/10.1038/nature07455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nguyen CT, Lu Q, Wang Y, Chen JN (2008) Zebrafish as a model for cardiovascular development and disease. Drug Discov Today Dis Model 5:135–140. https://doi.org/10.1016/j.ddmod.2009.02.003

    Article  Google Scholar 

  7. Jesulola E, Micalos P, Baguley IJ (2018) Understanding the pathophysiology of depression: from monoamines to the neurogenesis hypothesis model—are we there yet? Behav Brain Res 341:79–90. https://doi.org/10.1016/j.bbr.2017.12.025

    Article  CAS  PubMed  Google Scholar 

  8. Pariante CM, Lightman SL (2008) The HPA axis in major depression: classical theories and new developments. Trends Neurosci 31:464–468. https://doi.org/10.1016/j.tins.2008.06.006

    Article  CAS  PubMed  Google Scholar 

  9. Ferreira-Vieira H, Guimaraes TM, Silva F IR, Ribeiro M (2016) Alzheimer’s disease: targeting the cholinergic system. Curr Neuropharmacol 14:101–115. https://doi.org/10.2174/1570159x13666150716165726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Howe K, Clark MD, Torroja CF et al (2013) The zebrafish reference genome sequence and its relationship to the human genome. Nature 496:498–503. https://doi.org/10.1038/nature12111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pant J, Ranjan P, Deshpande SB (2011) Bisphenol A decreases atrial contractility involving NO-dependent G-cyclase signaling pathway. J Appl Toxicol 31:698–702. https://doi.org/10.1002/jat.1647

    Article  CAS  PubMed  Google Scholar 

  12. Heinonen IHA, Boushel R, Kalliokoski KK (2016) The circulatory and metabolic responses to hypoxia in humans—with special reference to adipose tissue physiology and obesity. Front Endocrinol (Lausanne) 7:1–6. https://doi.org/10.3389/fendo.2016.00116

    Article  Google Scholar 

  13. Becker JR, Deo RC, Werdich AA et al (2011) Human cardiomyopathy mutations induce myocyte hyperplasia and activate hypertrophic pathways during cardiogenesis in zebrafish. DMM Dis Model Mech 4:400–410. https://doi.org/10.1242/dmm.006148

    Article  CAS  PubMed  Google Scholar 

  14. Sahu MP, Pazos-Boubeta Y, Pajanoja C et al (2019) Neurotrophin receptor Ntrk2b function in the maintenance of dopamine and serotonin neurons in zebrafish. Sci Rep 9:1–13. https://doi.org/10.1038/s41598-019-39347-3

    Article  CAS  Google Scholar 

  15. Wullimann MF, Rink E (2001) Detailed immunohistology of Pax6 protein and tyrosine hydroxylase in the early zebrafish brain suggests role of Pax6 gene in development of dopaminergic diencephalic neurons. Dev Brain Res 131:173–191. https://doi.org/10.1016/S0165-3806(01)00270-X

    Article  CAS  Google Scholar 

  16. Thomson H (2017) Consistency of behaviours over time and context in zebrafish

  17. Baker MR, Goodman AC, Santo JB, Wong RY (2018) Repeatability and reliability of exploratory behavior in proactive and reactive zebrafish, Danio rerio. Sci Rep 8:1–9. https://doi.org/10.1038/s41598-018-30630-3

    Article  CAS  Google Scholar 

  18. Quintão TC, Rabelo LM, Alvarez TGS et al (2012) Zebrafish protocols for neurobehavioral research. Chemosphere 66:312–324. https://doi.org/10.1007/978-1-61779-597-8

    Article  Google Scholar 

  19. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-∆∆CT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  20. Parenti CC, Ghilardi A, Della Torre C et al (2019) Environmental concentrations of triclosan activate cellular defence mechanism and generate cytotoxicity on zebrafish (Danio rerio) embryos. Sci Total Environ 650:1752–1758. https://doi.org/10.1016/j.scitotenv.2018.09.283

    Article  CAS  PubMed  Google Scholar 

  21. Sárria MP, Soares J, Vieira MN et al (2011) Rapid-behaviour responses as a reliable indicator of estrogenic chemical toxicity in zebrafish juveniles. Chemosphere 85:1543–1547. https://doi.org/10.1016/j.chemosphere.2011.07.048

    Article  CAS  PubMed  Google Scholar 

  22. Zhao J, Zhang Q, Zhang B et al (2020) Developmental exposure to lead at environmentally relevant concentrations impaired neurobehavior and NMDAR-dependent BDNF signaling in zebrafish larvae. Environ Pollut 257:113627. https://doi.org/10.1016/j.envpol.2019.113627

    Article  CAS  PubMed  Google Scholar 

  23. Tsim K, Soreq H (2013) Acetylcholinesterase: old questions and new developments. Front Mol Neurosci 5:2012–2013. https://doi.org/10.3389/fnmol.2012.00101

    Article  Google Scholar 

  24. Dutta HM, Arends DA (2003) Effects of endosulfan on brain acetylcholinesterase activity in juvenile bluegill sunfish. Environ Res 91:157–162. https://doi.org/10.1016/S0013-9351(02)00062-2

    Article  CAS  PubMed  Google Scholar 

  25. Lionetto MG, Caricato R, Calisi A et al (2013) Acetylcholinesterase as a biomarker in environmental and occupational medicine: new insights and future perspectives. Biomed Res Int. https://doi.org/10.1155/2013/321213

    Article  PubMed  PubMed Central  Google Scholar 

  26. Picciotto MR, Higley MJ, Mineur YS (2012) Review acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76:116–129. https://doi.org/10.1016/j.neuron.2012.08.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rasier G, Parent AS, Gérard A et al (2008) Mechanisms of interaction of endocrine-disrupting chemicals with glutamate-evoked secretion of gonadotropin-releasing hormone. Toxicol Sci 102:33–41. https://doi.org/10.1093/toxsci/kfm285

    Article  CAS  PubMed  Google Scholar 

  28. Jenkins TA, Nguyen JCD, Polglaze KE, Bertrand PP (2016) Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutrients 8:1–15. https://doi.org/10.3390/nu8010056

    Article  CAS  Google Scholar 

  29. Booij L, Richard T, Szyf M, Benkelfat C (2015) Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology. J Psychiatry Neurosci 40:5–18. https://doi.org/10.1503/jpn.140099

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gao X, Wang H-S (2014) Impact of Bisphenol A on the cardiovascular system—epidemiological and experimental evidence and molecular mechanisms. Int J Environ Res Public Health 11:8399–8413. https://doi.org/10.3390/ijerph110808399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Papandreou I, Cairns RA, Fontana L et al (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197. https://doi.org/10.1016/j.cmet.2006.01.012

    Article  CAS  PubMed  Google Scholar 

  32. Sun L, Yu T, Guo J et al (2016) The estrogenicity of methylparaben and ethylparaben at doses close to the acceptable daily intake in immature Sprague-Dawley rats. Sci Rep 6:1–9. https://doi.org/10.1038/srep25173

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the students working in our laboratory have contributed to the collection of data required for this research work. We would also like to thank the Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India for providing us with the facilities for carrying out our work. We extend our gratitude to Usharani Balu, Poornima Ananthasubramanian, Sanjana Jayacumar, N. Jaswant Samuel, Deva Sureshbabu, S. Murli Krishnan, Sooriyakumar S, Sandhya Ramanan, Hamsini S, Vibha K, Keerthanah Sivakumar, Uma K Arun, and Maansi Srivastava.

Funding

The authors did not receive any financial support.

Author information

Authors and Affiliations

Authors

Contributions

ST executed the work, RV designed the experimental work, and BS helped in cross verification of data and statistical analysis.

Corresponding author

Correspondence to Vasantharekha Ramasamy.

Ethics declarations

Conflict of interest

The authors declare that there is no potential conflict of interest with respect to the research, authorship, and/or publication of this article. All authors read and approved the final manuscript.

Informed consent

Informed consent was obtained from all authors included in the study.

Research involving human and/or animal participants

This article does not contain any studies with human participants. Animal experimentation: Zebrafish handling was carried out in accordance with the ethical standards of the Institutional research committee and was ethically approved by the Institutional Animal Ethics Committee (IAEC) (project proposal number: SAF/210405/06) of SRM Engineering College, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thakkar, S., Seetharaman, B. & Ramasamy, V. Impact of chronic sub-lethal methylparaben exposure on cardiac hypoxia and alterations in neuroendocrine factors in zebrafish model. Mol Biol Rep 49, 331–340 (2022). https://doi.org/10.1007/s11033-021-06878-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06878-w

Keywords

Navigation