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Environmental Science and Pollution Research

, Volume 25, Issue 27, pp 26916–26926 | Cite as

Unraveling molecular targets of bisphenol A and S in the thyroid gland

  • Clemilson Berto-Júnior
  • Ana Paula Santos-Silva
  • Andrea Claudia Freitas Ferreira
  • Jones Bernades Graceli
  • Denise Pires de Carvalho
  • Paula Soares
  • Nelilma Correia Romeiro
  • Leandro Miranda-Alves
Research Article
  • 134 Downloads

Abstract

Bisphenol A (BPA) is a well-known endocrine disruptor with several effects on reproduction, development, and cancer incidence, and it is highly used in the plastic industry. Bisphenol S (BPS) was proposed as an alternative to BPA since it has a similar structure and can be used to manufacture the same products. Some reports show that BPA interferes with thyroid function, but little is known about the involvement of BPS in thyroid function or how these molecules could possibly modulate at the same time the principal genes involved in thyroid physiology. Thus, the aims of this work were to evaluate in silico the possible interactions of BPA and BPS with the thyroid transcription factors Pax 8 and TTF1 and to study the actions in vivo of these compounds in zebrafish thyroid gene expression. Adult zebrafish treated with BPA or BPS showed that sodium iodide symporter, thyroglobulin, and thyroperoxidase genes were negatively or positively regulated, depending on the dose of the exposure. Human Pax 8 alignment with zebrafish Pax 8 and Rattus norvegicus TTF1 alignment with zebrafish TTF1 displayed highly conserved regions in the DNA binding sites. Molecular docking revealed the in silico interactions between the protein targets Pax 8 and TTF1 with BPA and BPS. Importance of some amino acids residues is highlighted and ratified by literature. There were no differences between the mean energy values for BPA docking in Pax 8 or TTF1. However, BPS energy values were lower in TTF1 docking compared to Pax 8 values. The number of amino acids on the protein interface was important for Pax 8 but not for TTF1. The main BPA interactions with proteins occurred through Van der Waals forces and pi-alkyl and alkyl interactions, while BPS interactions mainly occurred through carbon hydrogen bonds and conventional hydrogen bonds in addition to Van der Waals forces and pi-alkyl interactions. These data point to a possible interaction of BPA and BPS with Pax 8 and TTF1.

Keywords

Bisphenol A Bisphenol S Thyroid PAX-8 TTF1 

Notes

Acknowledgements

We are very grateful to Prof. Dr. Silvana Allodi from IBCCF-UFRJ for making the invertebrate vivarium available and Silvania Nunes for technical assistance.

Compliance with ethical standards

The Ethics Committee for the Use of Animals (CEUA) of the Federal University of Rio de Janeiro approved all the procedures (number 045/14).

Conflict of interest

The authors declare that they have no conflict of interest.

Financial support

This study was supported by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (PP-SUS-FAPERJ E-26/110.282/2014; JCNE-FAPERJ, E-26/201.520/2014; APQ1-FAPERJ, E-26/111.485/2014), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Ciências sem Fronteiras/Pesquisador Visitante Especial/88881.062218/2014-0), and Conselho Nacional de Desenvolvimento Científico (CNPq, PQ- Nível 2, 305872/2016-8). Berto-Júnior scholarship and Ana Paula Santos-Silva fellowship were provided by CAPES. This research was also supported by FAPES No. 03/2017-UNIVERSAL (#179/2017) and CNPq No. 12/2017 (#304724/2017-3). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosure statement

No competing financial interests exist.

Supplementary material

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ESM 1

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High Resolution Image (TIF 49 kb)

References

  1. Ahmed S, Atlas E (2016) Bisphenol S- and bisphenol A-induced adipogenesis of murine preadipocytes occurs through direct peroxisome proliferator-activated receptor gamma activation. Int J Obes 40(10):1566–1573.  https://doi.org/10.1038/ijo.2016.95 CrossRefGoogle Scholar
  2. Barros TP, Alderton WK, Reynolds HM, Roach AG, Berghmans S (2008) Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery. Br J Pharmacol 154(7):1400–1413.  https://doi.org/10.1038/bjp.2008.249 CrossRefGoogle Scholar
  3. Bondesson M, Jönsson J, Pongratz I, Olea N, Cravedi JP, Zalko D, Håkansson H, Halldin K, Di Lorenzo D, Behl C et al (2009) A CASCADE of effects of bisphenol A. Reprod Toxicol 28:563–567.  https://doi.org/10.1016/j.reprotox.2009.06.014 CrossRefGoogle Scholar
  4. Carré A, Szinnai G, Castanet M, Sura-Trueba S, Tron E, Broutin-L’Hermite I et al (2009) Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Hum Mol Genet 18(12):2266–2276.  https://doi.org/10.1093/hmg/ddp162 CrossRefGoogle Scholar
  5. Carvalho DP, Dupuy C (2017) Thyroid hormone biosynthesis and release. Mol Cell Endocrinol S0303-7207(17):30051–30055.  https://doi.org/10.1016/j.mce.2017.01.038 CrossRefGoogle Scholar
  6. Carwile JL, Michels KB (2011) Urinary bisphenol A and obesity: NHANES 2003-2006. Environ Res 111:825–830.  https://doi.org/10.1016/j.envres.2011.05.014 CrossRefGoogle Scholar
  7. Champagne DL, Hoefnagels CC, de Kloet RE, Richardson MK (2010) Translating rodent behavioral repertoire to zebrafish (Danio rerio): relevance for stress research. Behav Brain Res 214(2):332–342CrossRefGoogle Scholar
  8. Chan WK, King MC (2012) Disruption of the hypothalamic-pituitary-thyroid axis in zebrafish embryo-larvae following waterborne exposure to BDE-47, TBBPA and BPA. Aquat Toxicol 108:106–111.  https://doi.org/10.1016/j.aquatox.2011.10.013 CrossRefGoogle Scholar
  9. Christophe D (2004) The control of thyroid-specific gene expression: what exactly have we learned as yet? Mol Cell Endocrinol 223(1–2):1–4CrossRefGoogle Scholar
  10. Codutti L, van Ingen H, Vascotto C, Fogolari F, Corazza A, Tell G, Quadrifoglio F, Viglino P, Boelens R, Esposito G (2008) The solution structure of DNA-free Pax-8 paired box domain accounts for redox regulation of transcriptional activity in the pax protein family. J Biol Chem 283(48):33321–33328.  https://doi.org/10.1074/jbc.M805717200
  11. Eladak S, Grisin T, Moison D, Guerguin NJ et al (2015) A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound. Fertil Steril 103(1):11–21.  https://doi.org/10.1016/j.fertnstert.2014.11.005 CrossRefGoogle Scholar
  12. Esposito C, Miccadei S, Saiardi A, Civitareale D (1998) PAX 8 activates the enhancer of the human thyroperoxidase gene. Biochem J 331(Pt 1):37–40CrossRefGoogle Scholar
  13. Fabbro D, Pellizzari L, Mercuri F, Tell G, Damante G (1998) Pax-8 protein levels regulate thyroglobulin gene expression. J Mol Endocrinol 21(3):347–354CrossRefGoogle Scholar
  14. Gebauer DL, Pagnussat N, Piato AL, Schaefer IC, Bonan CD, Lara DR (2011) Effects of anxiolytics in zebrafish: similarities and differences between benzodiazepines, buspirone and ethanol. Pharmacol Biochem Behav 99(3):480–486CrossRefGoogle Scholar
  15. Gerlai R (2010) High-throughput behavioral screens: the first step towards finding genes involved in vertebrate brain function using zebrafish. Molecules 15(4):2609–2622.  https://doi.org/10.3390/molecules15042609 CrossRefGoogle Scholar
  16. Kambe F, Seo H (1997) Thyroid-specific transcription factors. Endocr J 44(6):775–784CrossRefGoogle Scholar
  17. Kinch CD, Kingsley I, Joo-Hyun JHRH, Kurrasch DM (2015) Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish. Proc Natl Acad Sci U S A 112(5):1475–1480.  https://doi.org/10.1073/pnas.1417731112 CrossRefGoogle Scholar
  18. Kwon B, Kho Y, Kim PG, Ji K (2016) Thyroid endocrine disruption in male zebrafish following exposure to binary mixture of bisphenol AF and sulfamethoxazole. Environ Toxicol Pharmacol 48:168–174.  https://doi.org/10.1016/j.etap.2016.10.018 CrossRefGoogle Scholar
  19. Lee S, Kim C, Youn H, Choi K (2017) Thyroid hormone disrupting potentials of bisphenol A and its analogues—in vitro comparison study employing rat pituitary (GH3) and thyroid follicular (FRTL-5) cells. Toxicol in Vitro 40:297–304.  https://doi.org/10.1016/j.tiv.2017.02.004 CrossRefGoogle Scholar
  20. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408Google Scholar
  21. Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Fenzi G, Grüters A, Busslinger M, Lauro RD (1998) PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 19(1):83–86CrossRefGoogle Scholar
  22. Makarova K, Siudem P, Zawada K, Kurkoviak J (2016) Screening of toxic effects of bisphenol A and products of its degradation: zebrafish (Danio rerio) embryo test and molecular docking. Zebrafish 13(5):466–474.  https://doi.org/10.1089/zeb.2016.1261 CrossRefGoogle Scholar
  23. Manfo FP, Jubendradass R, Nantia EA, Moundipa PF, Mathur PP (2014) Adverse effects of bisphenol A on male reproductive function. Rev Environ Contam Toxicol 228:57–82.  https://doi.org/10.1007/978-3-319-01619-1_3 CrossRefGoogle Scholar
  24. Maserejian NN, Trachtenberg FL, Hauser R, McKinlay S, Shrader P, Tavares M, Bellinger DC (2012) Dental composite restorations and psychosocial function in children. Pediatrics 130:e328–e338.  https://doi.org/10.1542/peds.2011-3374 CrossRefGoogle Scholar
  25. Melzer D, Gates P, Osborn NJ, Henley WE, Cipelli R, Young A, Money C, McCormack P, Schofield P, Mosedale D, Grainger D, Galloway TS (2012) Urinary bisphenol A concentration and angiography-defined coronary artery stenosis. PLoSOne 7(8):e43378.  https://doi.org/10.1371/journal.pone.0043378 CrossRefGoogle Scholar
  26. Michalowicz J (2014) Bisphenol A—sources, toxicity and biotransformation. Environ Toxicol Pharmacol 37(2):738–758.  https://doi.org/10.1016/j.etap.2014.02.003 CrossRefGoogle Scholar
  27. Molina AM, Lora AJ, Blanco A, Monterde JG, Ayala N, Moyano R (2013) Endocrine-active compound evaluation: qualitative and quantitative histomorphological assessment of zebrafish gonads after bisphenol-A exposure. Ecotoxicol Environ Saf 88:155–162.  https://doi.org/10.1016/j.ecoenv.2012.11.010 CrossRefGoogle Scholar
  28. Montanelli L, Tonacchera M (2010) Genetics and phenomics of hypothyroidism and thyroid dys- and agenesis due to PAX8 and TTF1 mutations. Mol Cell Endocrinol 322(1–2):64–71.  https://doi.org/10.1016/j.mce.2010.03.009 CrossRefGoogle Scholar
  29. Moriyama K, Tagami T, Akamizu T, Saijo M, Kanamoto N, Hataya Y, Shimatzu A, Kuzuya H, Nakao K (2002) Thyroid hormone action is disrupted by bisphenol A as an antagonist. J Clin Endocrinol Metab 87(11):5185–5190CrossRefGoogle Scholar
  30. Narumi S, Araki S, Hori N, Muroya K, Yamamoto Y, Asakura Y, Adachi M, Hasegawa T (2012) Functional characterization of four novel PAX8 mutations causing congenital hypothyroidism: new evidence for haploinsufficiency as a disease mechanism. Eur J Endocrinol 167(5):625–632.  https://doi.org/10.1530/EJE-12-0410 CrossRefGoogle Scholar
  31. Panigrahi SK, Desiraju GR (2007) Strong and week hydrogen bonds in drug-DNA complexes: a statistical analysis. J Biosci 32(4):677–691CrossRefGoogle Scholar
  32. Pellizzari L, Tell G, Damante G (1999) Co-operation between the PAI and RED subdomains of Pax-8 in the interaction with the thyroglobulin promoter. Biochem J 337(Pt 2):253–262CrossRefGoogle Scholar
  33. Philippat C, Mortamais M, Chevrier C, Petit C, Calafat AM, Ye X, Silva MJ, Brambilla C, Pin I, Charles MA, Cordier S, Slama R (2012) Exposure to phthalates and phenols during pregnancy and offspring size at birth. Environ Health Perspect 120:464–470.  https://doi.org/10.1289/ehp.1103634 CrossRefGoogle Scholar
  34. Porazzi P, Calebiro D, Benato F, Tiso N, Persani L (2009) Thyroid gland development and function in the zebrafish model. Mol Cell Endocrinol 312(1–2):14–23.  https://doi.org/10.1016/j.mce.2009.05.011 CrossRefGoogle Scholar
  35. Ramos HE, Carré A, Chevrier L, Sznnai G, Tron E et al (2014) Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations. Eur J Endocrinol 171(4):499–507.  https://doi.org/10.1530/EJE-13-1006 CrossRefGoogle Scholar
  36. Rochester JR (2013) Bisphenol A and human health: a review of the literature. Reprod Toxicol 42:132–155.  https://doi.org/10.1016/j.reprotox.2013.08.008 CrossRefGoogle Scholar
  37. Rosenmai AK, Dybdahl M, Pedersen M, Alice van Vugt-Lussenburg BM, Wedebye AB, Taxvig C, Vinggaard AM (2014) Are structural analogues to bisphenol a safe alternatives? Toxicol Sci 139(1):35–47.  https://doi.org/10.1093/toxsci/kfu030 CrossRefGoogle Scholar
  38. Schug T, Janesick A, Blumberg B, Heindel J (2011) Endocrine disrupting chemicals and disease susceptibility. J Steroid Biochem Mol Biol 127:204–211.  https://doi.org/10.1016/j.jsbmb.2011.08.007 CrossRefGoogle Scholar
  39. Spence R, Gerlach G, Lawrence C, Smith C (2008) The behaviour and ecology of the zebrafish, Danio rerio. Biol Rev Camb Philos Soc 83(1):13–34.  https://doi.org/10.1111/j.1469-185X.2007.00030.x CrossRefGoogle Scholar
  40. Sumanas S, Jorniak T, Lin S (2005) Identification of novel vascular endothelial-specific genes by the microarray analysis of the zebrafish cloche mutants. Blood 106(2):534–541.  https://doi.org/10.1182/blood-2004-12-4653 CrossRefGoogle Scholar
  41. Terrien X, Jean-Baptiste FBA, Demeneix KWS, Patrick P (2011) Generation of fluorescent zebrafish to study endocrine disruption and potential crosstalk between thyroid hormone and corticosteroids. Aquat Toxicol 105(1–2):13–20.  https://doi.org/10.1016/j.aquatox.2011.04.007 CrossRefGoogle Scholar
  42. Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, DRJr J, Lee DH, Shioda T, Soto AM, vom Saal FS, Welshons WV, Zoeller RT, Myers JP (2012) Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev 33(3):378–455.  https://doi.org/10.1210/er.2011-105033 CrossRefGoogle Scholar
  43. Vicenzi M, Camilot M, Ferrarini E, Teofoli F, Venturi G, Gaudino R, Cavarzere P, De Marco G, Agretti P, Dimida A, Tonacchera M, Boner A, Antoniazzi F (2014) Identification of a novel pax 8 gene sequence variant in four members of the same family: from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism. BMC Endocr Disord 22:14–69.  https://doi.org/10.1186/1472-6823-14-69 CrossRefGoogle Scholar
  44. Yang M, Ryu JH, Jeon R, Kang D, Yoo KY (2009) Effects of bisphenol A on breast cancer and its risk factors. Arch Toxicol 83:281–285.  https://doi.org/10.1007/s00204-008-0364-0 CrossRefGoogle Scholar
  45. Yang O, Kim HL, Weon JI, Seo YR (2015) Endocrine-disrupting chemicals: review of toxicological mechanisms using molecular pathway analysis. J Cancer Prev 20(1):12–24.  https://doi.org/10.15430/JCP.2015.20.1.12 CrossRefGoogle Scholar
  46. Zhang DH, Zhou EX, Yang ZL (2017a) Waterborne exposure to BPS causes thyroid endocrine disruption in zebrafish larvae. PLoS One 12(5):e0176927.  https://doi.org/10.1371/journal.pone.0176927 CrossRefGoogle Scholar
  47. Zhang YF, Xiao-Min R, Yuan-Yuan L, Xiao-Fang Y, Chuan-Hai L, Zhan-Fen Q, Liang-Hong G (2017b) Bisphenol A alternatives bisphenol S and bisphenol F interfere with thyroid hormone signaling pathway in vitro and in vivo. Environ Pollut S0269-7491(17):33580–33587.  https://doi.org/10.1016/j.envpol.2017.11.027 CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Clemilson Berto-Júnior
    • 1
    • 2
    • 3
  • Ana Paula Santos-Silva
    • 1
    • 3
  • Andrea Claudia Freitas Ferreira
    • 1
    • 2
    • 3
    • 4
  • Jones Bernades Graceli
    • 5
  • Denise Pires de Carvalho
    • 1
    • 2
    • 3
  • Paula Soares
    • 6
    • 7
    • 8
    • 9
  • Nelilma Correia Romeiro
    • 10
  • Leandro Miranda-Alves
    • 1
    • 2
    • 11
  1. 1.Grupo de Pesquisa, Desenvolvimento e Inovação em Endocrinologia Experimental-GPDIEEx, Instituto de Ciências BiomédicasUniversidade Federal do Rio de Janeiro, BrazilRio de JaneiroBrazil
  2. 2.Pós-graduação em Endocrinologia, Faculdade de MedicinaUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil
  3. 3.Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil
  4. 4.Polo de Xerém/NUMPEXUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil
  5. 5.Laboratório de Endocrinologia e Toxicologia Celular, Departamento de MorfologiaUniversidade Federal do Espírito SantoVitóriaBrazil
  6. 6.Institute for Research and Innovation in HealthUniversity of PortoPortoPortugal
  7. 7.Cancer BiologyInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)PortoPortugal
  8. 8.Medical FacultyUniversity of PortoPortoPortugal
  9. 9.Department of Pathology and Oncology, Medical FacultyPorto UniversityPortoPortugal
  10. 10.Núcleo de Pesquisas em Ecologia e Desenvolvimento Socioambiental de MacaéUniversidade Federal do Rio de JaneiroMacaéBrazil
  11. 11.Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências BiomédicasUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil

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