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.
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References
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
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
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
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
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
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
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):332–342
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
Christophe D (2004) The control of thyroid-specific gene expression: what exactly have we learned as yet? Mol Cell Endocrinol 223(1–2):1–4
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
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
Esposito C, Miccadei S, Saiardi A, Civitareale D (1998) PAX 8 activates the enhancer of the human thyroperoxidase gene. Biochem J 331(Pt 1):37–40
Fabbro D, Pellizzari L, Mercuri F, Tell G, Damante G (1998) Pax-8 protein levels regulate thyroglobulin gene expression. J Mol Endocrinol 21(3):347–354
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):480–486
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
Kambe F, Seo H (1997) Thyroid-specific transcription factors. Endocr J 44(6):775–784
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
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
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
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):402–408
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):83–86
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
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
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
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
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
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
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
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):5185–5190
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
Panigrahi SK, Desiraju GR (2007) Strong and week hydrogen bonds in drug-DNA complexes: a statistical analysis. J Biosci 32(4):677–691
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):253–262
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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We are very grateful to Prof. Dr. Silvana Allodi from IBCCF-UFRJ for making the invertebrate vivarium available and Silvania Nunes for technical assistance.
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The Ethics Committee for the Use of Animals (CEUA) of the Federal University of Rio de Janeiro approved all the procedures (number 045/14).
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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.
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Berto-Júnior, C., Santos-Silva, A.P., Ferreira, A.C.F. et al. Unraveling molecular targets of bisphenol A and S in the thyroid gland. Environ Sci Pollut Res 25, 26916–26926 (2018). https://doi.org/10.1007/s11356-018-2419-y
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DOI: https://doi.org/10.1007/s11356-018-2419-y