Unraveling molecular targets of bisphenol A and S in the thyroid gland
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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.
KeywordsBisphenol A Bisphenol S Thyroid PAX-8 TTF1
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.
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.
No competing financial interests exist.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 Google Scholar
- 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 Google Scholar