Skip to main content
SpringerLink
Log in

IR-MALDESI mass spectrometry imaging of underivatized neurotransmitters in brain tissue of rats exposed to tetrabromobisphenol A

  • Research Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

There is a pressing need to develop tools for assessing possible neurotoxicity, particularly for chemicals where the mode of action is poorly understood. Tetrabromobisphenol A (TBBPA), a highly abundant brominated flame retardant, has lately been targeted for neurotoxicity analysis by concerned public health entities in the EU and USA because it is a suspected thyroid disruptor and neurotoxicant. In this study, infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) coupled to a Q Exactive Plus mass spectrometer was used for the analysis of neurotransmitters in the brains of rats exposed to TBBPA in gestation and lactation through their mothers. Three neurotransmitters of interest were studied in three selected regions of the brain: caudate putamen, substantia nigra (SN), and dorsal raphe. Stable isotope labeled (SIL) standards were used as internal standards and a means to achieve relative quantification. This study serves as a demonstration of a new application of IR-MALDESI, namely that neurotransmitter distributions can be confidently and rapidly imaged without derivatization.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Galanopoulou AS. Sexually dimorphic expression of KCC2 and GABA function. Epilepsy Res. 2008. https://doi.org/10.1016/j.eplepsyres.2008.04.013.

    Article  CAS  Google Scholar 

  2. How many chemicals are in use today? C&EN Global Enterp. 2017. https://doi.org/10.1021/cen-09509-govpol.

  3. Heyer DB, Meredith RM. Environmental toxicology: sensitive periods of development and neurodevelopmental disorders. Neurotoxicology. 2017.

  4. Malliari E, Kalantzi O. Children’s exposure to brominated flame retardants in indoor environments - a review. Environ Int. 2017;108:146–69.

    Article  CAS  Google Scholar 

  5. Sugeng EJ, de Cock M, Schoonmade LJ, van de Bor M. Toddler exposure to flame retardant chemicals: magnitude, health concern and potential risk- or protective factors of exposure: observational studies summarized in a systematic review. Chemosphere. 2017;184:820–31.

    Article  CAS  Google Scholar 

  6. Dingemans MML, van dB, Westerink RHS. Neurotoxicity of brominated flame retardants: (in)direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system. Environ Health Perspect. 2011. https://doi.org/10.1289/ehp.1003035.

    Article  CAS  Google Scholar 

  7. Stapleton HM, Sharma S, Getzinger G, Ferguson PL, Gabriel M, Webster TF, et al. Novel and high volume use flame retardants in US couches reflective of the 2005 PentaBDE phase out. Environ Sci Technol. 2012. https://doi.org/10.1021/es303471d.

    Article  CAS  Google Scholar 

  8. Knudsen GA, Hughes MF, McIntosh KL, Sanders JM, Birnbaum LS. Estimation of tetrabromobisphenol A (TBBPA) percutaneous uptake in humans using the parallelogram method. Toxicol Appl Pharmacol. 2015. https://doi.org/10.1016/j.taap.2015.09.012.

    Article  CAS  Google Scholar 

  9. Antignac JP, Cariou R, Zalko D, Berrebi A, Cravedi JP, Maume D, et al. Exposure assessment of French women and their newborn to brominated flame retardants: determination of tri- to deca- polybromodiphenylethers (PBDE) in maternal adipose tissue, serum, breast milk and cord serum. Environ Pollut. 2009. https://doi.org/10.1016/j.envpol.2008.07.008.

    Article  CAS  Google Scholar 

  10. Cariou R, Antignac JP, Zalko D, Berrebi A, Cravedi JP, Maume D, et al. Exposure assessment of French women and their newborns to tetrabromobisphenol-A: occurrence measurements in maternal adipose tissue, serum, breast milk and cord serum. Chemosphere. 2008. https://doi.org/10.1016/j.chemosphere.2008.07.084.

    Article  CAS  Google Scholar 

  11. Lai DY, Kacew S, Dekant W. Tetrabromobisphenol A (TBBPA): possible modes of action of toxicity and carcinogenicity in rodents. Food Chem Toxicol. 2015. https://doi.org/10.1016/j.fct.2015.03.023.

    Article  CAS  Google Scholar 

  12. National TP. NTP technical report on the toxicology studies of tetrabromobisphenol A (CASRN 79-94-7) in F344/NTac rats and B6C3F1/N mice and toxicology and carcinogenesis studies of tetrabromobisphenol A in Wistar Han Crl:WI(Han)] rats and B6C3F1/N mice (gavage studies). U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Toxicology Program. 2014.

  13. Nakajima A, Saigusa D, Tetsu N, Yamakuni T, Tomioka Y, Hishinuma T. Neurobehavioral effects of tetrabromobisphenol A, a brominated flame retardant, in mice. Toxicol Lett. 2009. https://doi.org/10.1016/j.toxlet.2009.05.003.

    Article  CAS  Google Scholar 

  14. Chughtai K, Heeren RMA. Mass spectrometric imaging for biomedical tissue analysis. Chem Rev. 2010. https://doi.org/10.1021/cr100012c.

    Article  CAS  Google Scholar 

  15. Tanaka K, Waki H, Ido Y, Akita S, Yoshida Y, Yoshida T, et al. Protein and polymer analyses up to m/z 100 000 by laser ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom. 1988. https://doi.org/10.1002/rcm.1290020802.

    Article  CAS  Google Scholar 

  16. Karas M, Hillenkamp F. Laser desorption ionization of proteins with molecular masses exceeding 10,000 daltons. Anal Chem. 1988. https://doi.org/10.1021/ac00171a028.

    Article  CAS  Google Scholar 

  17. Fenn JB, Mann M, Meng CK, Wong SF, Whitehouse CM. Electrospray ionization for mass spectrometry of large biomolecules. Science. 1989. https://doi.org/10.1126/science.2675315.

    Article  CAS  Google Scholar 

  18. Norris JL, Caprioli RM. Analysis of tissue specimens by matrix-assisted laser desorption/ionization imaging mass spectrometry in biological and clinical research. Chem Rev. 2013. https://doi.org/10.1021/cr3004295.

    Article  CAS  Google Scholar 

  19. Shariatgorji M, Nilsson A, Goodwin RJ, Kallback P, Schintu N, Zhang X, et al. Direct targeted quantitative molecular imaging of neurotransmitters in brain tissue sections. Neuron. 2014. https://doi.org/10.1016/j.neuron.2014.10.011.

    Article  CAS  Google Scholar 

  20. Nemes P, Woods AS, Vertes A. Simultaneous imaging of small metabolites and lipids in rat brain tissues at atmospheric pressure by laser ablation electrospray ionization mass spectrometry. Anal Chem. 2010. https://doi.org/10.1021/ac902245p.

    Article  CAS  Google Scholar 

  21. Bergman HM, Lundin E, Andersson M, Lanekoff I. Quantitative mass spectrometry imaging of small-molecule neurotransmitters in rat brain tissue sections using nanospray desorption electrospray ionization. Analyst. 2016. https://doi.org/10.1039/c5an02620b.

    Article  CAS  Google Scholar 

  22. Fernandes AMAP, Vendramini PH, Galaverna R, Schwab NV, Alberici LC, Augusti R, et al. Direct visualization of neurotransmitters in rat brain slices by desorption electrospray ionization mass spectrometry imaging (DESI - MS). J Am Soc Mass Spectrom. 2016. https://doi.org/10.1007/s13361-016-1475-0.

    Article  CAS  Google Scholar 

  23. Passarelli MK, Winograd N. Lipid imaging with time-of-flight secondary ion mass spectrometry (ToF-SIMS). Biochim Biophys Acta. 2011. https://doi.org/10.1016/j.bbalip.2011.05.007.

    Article  CAS  Google Scholar 

  24. Bokhart MT, Muddiman DC. Infrared matrix-assisted laser desorption electrospray ionization mass spectrometry imaging analysis of biospecimens. Analyst. 2016. https://doi.org/10.1039/c6an01189f.

    Article  CAS  Google Scholar 

  25. Robichaud G, Barry J, Muddiman D. IR-MALDESI mass spectrometry imaging of biological tissue sections using ice as a matrix. J Am Soc Mass Spectrom. 2014. https://doi.org/10.1007/s13361-013-0787-6.

    Article  CAS  Google Scholar 

  26. Esteve C, Tolner EA, Shyti R, van dM, McDonnell LA. Mass spectrometry imaging of amino neurotransmitters: a comparison of derivatization methods and application in mouse brain tissue. Metabolomics. 2016. https://doi.org/10.1007/s11306-015-0926-0.

  27. Sakino T, Yuki S, Akiko K, Mitsuyo O, Sachise K, Toshimi M, et al. Microscopic imaging mass spectrometry assisted by on-tissue chemical derivatization for visualizing multiple amino acids in human colon cancer xenografts. Proteomics. 2014. https://doi.org/10.1002/pmic.201300041.

    Article  Google Scholar 

  28. Shariatgorji M, Nilsson A, Goodwin RA, Källback P, Schintu N, Zhang X, et al. Direct targeted quantitative molecular imaging of neurotransmitters in brain tissue sections. Neuron. 2014;84:697–707.

    Article  CAS  Google Scholar 

  29. Bokhart MT, Rosen E, Thompson C, Sykes C, Kashuba ADM, Muddiman DC. Quantitative mass spectrometry imaging of emtricitabine in cervical tissue model using infrared matrix-assisted laser desorption electrospray ionization. Anal Bioanal Chem. 2015. https://doi.org/10.1007/s00216-014-8220-y.

    Article  Google Scholar 

  30. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. London: Academic Press; 2007.

    Google Scholar 

  31. Arambula SE, Fuchs J, Cao J, Patisaul HB. Effects of perinatal bisphenol A exposure on the volume of sexually-dimorphic nuclei of juvenile rats: a CLARITY-BPA consortium study. NeuroToxicology. 2017;63:33–42.

    Article  CAS  Google Scholar 

  32. Cao J, Joyner L, Mickens JA, Leyrer SM, Patisaul HB. Sex-specific Esr2 mRNA expression in the rat hypothalamus and amygdala is altered by neonatal bisphenol A exposure. Reproduction. 2014. https://doi.org/10.1530/rep-13-0501.

    Article  CAS  Google Scholar 

  33. Ekelöf M, Manni J, Nazari M, Bokhart M, Muddiman DC. Characterization of a novel miniaturized burst-mode infrared laser system for IR-MALDESI mass spectrometry imaging. Anal Bioanal Chem. 2018. https://doi.org/10.1007/s00216-018-0918-9.

    Article  Google Scholar 

  34. Robichaud G, Garrard KP, Barry JA, Muddiman DC. MSiReader: an open-source interface to view and analyze high resolving power MS imaging files on Matlab platform. J Am Soc Mass Spectrom. 2013. https://doi.org/10.1007/s13361-013-0607-z.

    Article  CAS  Google Scholar 

  35. Bokhart MT, Nazari M, Garrard KP, Muddiman DC. MSiReader v1.0: evolving open-source mass spectrometry imaging software for targeted and untargeted analyses. J Am Soc Mass Spectrom. 2017. https://doi.org/10.1007/s13361-017-1809-6.

    Article  Google Scholar 

  36. Chambers MC, Maclean B, Burke R, Amodei D, Ruderman DL, Neumann S, et al. A cross-platform toolkit for mass spectrometry and proteomics. Nat Biotechnol. 2012. https://doi.org/10.1038/nbt.2377.

    Article  CAS  Google Scholar 

  37. Race AM, Styles IB, Bunch J. Inclusive sharing of mass spectrometry imaging data requires a converter for all. J Proteomics. 2012. https://doi.org/10.1016/j.jprot.2012.05.035.

    Article  CAS  Google Scholar 

  38. Hines M, Allen LS, Gorski RA. Sex differences in subregions of the medial nucleus of the amygdala and the bed nucleus of the stria terminalis of the rat. Brain Res. 1992;579:321–6.

    Article  CAS  Google Scholar 

  39. Frazer A, Hensler JG. Anonymous basic neurochemistry molecular, cellular and medical aspects. 6th ed. Philadelphia: Lippincott-Raven; 1999.

    Google Scholar 

  40. Yu X, Ye Z, Houston C, Zecharia A, Ma Y, Zhang Z, et al. Wakefulness is governed by GABA and histamine cotransmission. Neuron. 2015. https://doi.org/10.1016/j.neuron.2015.06.003.

    Article  CAS  Google Scholar 

  41. Ponvert C, Galoppin L, Scheinmann P, Canu P, Burtin C. Tissue histamine levels in male and female mast cell deficient mice (W/Wv) and in their littermates (Wv/+, W/+ and +/+). Agents Actions. 1985. https://doi.org/10.1007/BF01966671.

    Article  CAS  Google Scholar 

  42. Netter KJ, Cohn VH, Shore PA. Sex difference in histamine metabolism in the rat. Am J Physiol. 1961. https://doi.org/10.1152/ajplegacy.1961.201.2.224.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

All mass spectrometry measurements were made in the Molecular Education, Technology, and Research Innovation Center (METRIC) at NC State University. We are grateful for the NIEHS research team who designed and executed the TBBPA exposure portion of this project, especially Suzanne Fenton, Manushree Bharadwaj, Joshua Warmack, and Sagi Enicole Gillera.

Funding

This study received financial assistance from the National Institutes of Health grants R01GM087964 (MCB, ME, DM) and P30ES025128 to North Carolina State University as well as a National Institutes of Health IPA Agreement with HP.

Author information

Authors and Affiliations

  1. FTMS Laboratory for Human Health Research, Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA

    M. Caleb Bagley, Måns Ekelöf & David C. Muddiman

  2. Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA

    Kylie Rock & Heather Patisaul

  3. Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27691, USA

    Kylie Rock, Heather Patisaul & David C. Muddiman

  4. Molecular Education, Technology and Research Innovation Center (METRIC), North Carolina State University, Raleigh, NC, 27695, USA

    David C. Muddiman

Authors
  1. M. Caleb Bagley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Måns Ekelöf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kylie Rock
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heather Patisaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David C. Muddiman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David C. Muddiman.

Ethics declarations

All aspects of the rat studies were approved by the Institutional Animal Care and Use Committees of NIEHS and NCSU.

Conflict of interest

The authors declare that they have no conflicts of interest

Electronic supplementary material

ESM 1

(PDF 3448 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bagley, M.C., Ekelöf, M., Rock, K. et al. IR-MALDESI mass spectrometry imaging of underivatized neurotransmitters in brain tissue of rats exposed to tetrabromobisphenol A. Anal Bioanal Chem 410, 7979–7986 (2018). https://doi.org/10.1007/s00216-018-1420-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-018-1420-0

Keywords

Search

Navigation