Binding interaction of typical emerging contaminants on Gobiocypris rarus transthyretin: an in vitro and in silico study

Highlights

● Potential binding potency of 29 ECs on Gobiocypris rarus transthyretin were tested.

● The Gobiocypris rarus TTR binding affinity of 3 ECs was higher than that of T₄.

● High throughput screening classification models for fish and human TTR were derived.

● “TTR Profiler” can predict the potential fish and human TTR disrupting effects data.

Abstract

Emerging contaminants (ECs) have drawn global concern, and the endocrine disrupting chemicals is one of the highly interested ECs categories. However, numerous ECs lacks the basic information about whether they can disturb the endocrine related biomacromolecules or elicit endocrine related detrimental effects on organism. In this study, the potential binding affinity and underlying binding mechanism between 29 ECs from 7 chemical groups and Gobiocypris rarus transthyretin (CrmTTR) are investigated and probed using in vitro and in silico methods. The experimental results demonstrate that 14 selected ECs (11 disinfection byproducts, 1 pharmaceuticals and personal care product, 1 alkylphenol, 1 perfluoroalkyl and polyfluoroalkyl substance) are potential CrmTTR binders. The CrmTTR binding affinity of three ECs (i.e., 2,6-diiodo-4-nitrophenol (logRP(T₄) = 0.678 ± 0.198), 2-bromo-6-chloro-4-nitrophenol (logRP(T₄) = 0.399 ± 0.0908), tetrachloro-1,4-benzoquinone (logRP(T₄) = 0.272 ± 0.0655)) were higher than that of 3,3′,5,5′-tetraiodo-L-thyronine, highlighting that more work should be performed to reveal their potential endocrine related harmful effects on Gobiocypris rarus. Molecular docking results imply that hydrogen bond and hydrophobic interactions are the dominated non-covalent interactions between the active disruptors and CrmTTR. The optimum mechanism-based (for CrmTTR), and high throughput screening (for CrmTTR, little skate-TTR, seabream-TTR, and human-TTR) binary classification models are developed using three machine learning algorithms, and all the models have good classification performance. To facilitate the use of developed high throughput screening models, a tool named “TTR Profiler” is derived, which could be employed to determine whether a given substance is a potential CrmTTR, little skate-TTR, seabream-TTR, or human-TTR disruptor or not.

Graphical abstract

Keywords

Endocrine disrupting effects / Hormone transporter / Endocrine disrupting chemicals / Disinfection byproducts / Classification model

References

[1] Archer E, Petrie B, Kasprzyk-Hordern B, Wolfaardt G M. (2017). The fate of pharmaceuticals and personal care products (PPCPs), endocrine disrupting contaminants (EDCs), metabolites and illicit drugs in a WWTW and environmental waters. Chemosphere, 174: 437–446

[2] Bodor N, Gabanyi Z, Wong C K. (1989). A new method for the estimation of partition coefficient. Journal of the American Chemical Society, 111(11): 3783–3786

[3] Bodor N, Huang M J. (1992). An extended version of a novel method for the estimation of partition coefficients. Journal of Pharmaceutical Sciences, 81(3): 272–281

[4] Cao H, Zhou Z, Wang L, Liu G, Sun Y, Wang Y, Wang T, Liang Y. (2019). Screening of potential PFOS alternatives to decrease liver bioaccumulation: experimental and computational approaches. Environmental Science & Technology, 53(5): 2811–2819

[5] Collet B, Simon E, Van Der Linden S, El Abdellaoui N, Naderman M, Man H Y, Middelhof I, Van Der Burg B, Besselink H, Brouwer A. (2020). Evaluation of a panel of in vitro methods for assessing thyroid receptor β and transthyretin transporter disrupting activities. Reproductive Toxicology, 96: 432–444

[6] Dracheva E, Norinder U, Rydén P, Engelhardt J, Weiss J M, Andersson P L. (2022). In silico identification of potential thyroid hormone system disruptors among chemicals in human serum and chemicals with a high exposure index. Environmental Science & Technology, 56(12): 8363–8372

[7] FrischM J, Trucks G W, SchlegelH B, ScuseriaG E, RobbM A, CheesemanJ R, ScalmaniG, BaroneV, PeterssonG A, NakatsujiH, et al. (2016). Gaussian 16 Revision C.01. Wallingford CT: Gaussian, Inc.

[8] Garcia de Lomana M, Weber A G, Birk B, Landsiedel R, Achenbach J, Schleifer K J, Mathea M, Kirchmair J. (2021). In silico models to predict the perturbation of molecular initiating events related to thyroid hormone homeostasis. Chemical Research in Toxicology, 34(2): 396–411

[9] Hamers T, Kamstra J H, Sonneveld E, Murk A J, Kester M H A, Andersson P L, Legler J, Brouwer A. (2006). In vitro profiling of the endocrine-disrupting potency of brominated flame retardants. Toxicological Sciences, 92(1): 157–173

[10] He J, Xu J, Zheng M, Pan K, Yang L, Ma L, Wang C, Yu J. (2024). Thyroid dysfunction caused by exposure to environmental endocrine disruptors and the underlying mechanism: a review. Chemico-Biological Interactions, 391: 110909

[11] Hong H, Branham W S, Ng H W, Moland C L, Dial S L, Fang H, Perkins R, Sheehan D, Tong W. (2015). Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein. Toxicological Sciences, 143(2): 333–348

[12] Ishihara A, Nishiyama N, Sugiyama S I, Yamauchi K. (2003). The effect of endocrine disrupting chemicals on thyroid hormone binding to Japanese quail transthyretin and thyroid hormone receptor. General and Comparative Endocrinology, 134(1): 36–43

[13] James C A, Sofield R, Faber M, Wark D, Simmons A, Harding L, O’Neill S. (2023). The screening and prioritization of contaminants of emerging concern in the marine environment based on multiple biological response measures. Science of the Total Environment, 886: 163712

[14] Janssen S T, Janssen O E. (2017). Directional thyroid hormone distribution via the blood stream to target sites. Molecular and Cellular Endocrinology, 458: 16–21

[15] Langberg H A, Choyke S, Hale S E, Koekkoek J, Cenijn P H, Lamoree M H, Rundberget T, Jartun M, Breedveld G D, Jenssen B M. . (2024). Effect-directed analysis based on transthyretin binding activity of per- and polyfluoroalkyl substances in a contaminated sediment extract. Environmental Toxicology and Chemistry, 43(2): 245–258

[16] Laskowski R A, Swindells M B. (2011). LigPlot+: multiple ligand–protein interaction diagrams for drug discovery. Journal of Chemical Information and Modeling, 51(10): 2778–2786

[17] Li Y, Zhang Z, Wang J, Shan Y, Tian H, Cui P, Ru S. (2023). Zebrafish (Danio rerio) TRβ- and TTR-based electrochemical biosensors: construction and application for the evaluation of thyroid-disrupting activity of bisphenols. Environmental Pollution, 330: 121745

[18] Lin X, Xu J, Keller A A, He L, Gu Y, Zheng W, Sun D, Lu Z, Huang J, Huang X. . (2020). Occurrence and risk assessment of emerging contaminants in a water reclamation and ecological reuse project. Science of the Total Environment, 744: 140977

[19] Liu S S, You W D, Chen C E, Wang X Y, Yang B, Ying G G. (2023a). Occurrence, fate and ecological risks of 90 typical emerging contaminants in full-scale textile wastewater treatment plants from a large industrial park in Guangxi, Southwest China. Journal of Hazardous Materials, 449: 131048

[20] Liu W, Wang Z, Chen J, Tang W, Wang H. (2023b). Machine learning model for screening thyroid stimulating hormone receptor agonists based on updated datasets and improved applicability domain metrics. Chemical Research in Toxicology, 36(6): 947–958

[21] Marchesini G R, Meimaridou A, Haasnoot W, Meulenberg E, Albertus F, Mizuguchi M, Takeuchi M, Irth H, Murk A J. (2008). Biosensor discovery of thyroxine transport disrupting chemicals. Toxicology and Applied Pharmacology, 232(1): 150–160

[22] Morgado I, Hamers T, Van Der Ven L, Power D M. (2007). Disruption of thyroid hormone binding to sea bream recombinant transthyretin by ioxinyl and polybrominated diphenyl ethers. Chemosphere, 69(1): 155–163

[23] Prapunpoj P, Leelawatwattana L. (2009). Evolutionary changes to transthyretin: structure–function relationships. FEBS Journal, 276(19): 5330–5341

[24] Ren X M, Yao L, Xue Q, Shi J, Zhang Q, Wang P, Fu J, Zhang A, Qu G, Jiang G. (2020). Binding and activity of tetrabromobisphenol A mono-ether structural analogs to thyroid hormone transport proteins and receptors. Environmental Health Perspectives, 128(10): 107008

[25] RichardsonS J (2015). Tweaking the structure to radically change the function: the evolution of transthyretin from 5-hydroxyisourate hydrolase to triiodothyronine distributor to thyroxine distributor. Frontiers in Endocrinology, 5: 245

[26] Sakkiah S, Guo W, Pan B, Kusko R, Tong W, Hong H. (2018). Computational prediction models for assessing endocrine disrupting potential of chemicals. Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews, 36(4): 192–218

[27] Simon E, Bytingsvik J, Jonker W, Leonards P E G, De Boer J, Jenssen B M, Lie E, Aars J, Hamers T, Lamoree M H. (2011). Blood plasma sample preparation method for the assessment of thyroid hormone-disrupting potency in effect-directed analysis. Environmental Science & Technology, 45(18): 7936–7944

[28] Su H, Zhang Q, Huang K, Wang W X, Li H, Huang Z, Cheng F, You J. (2023). Two-compartmental toxicokinetic model predicts interspecies sensitivity variation of imidacloprid to aquatic invertebrates. Environmental Science & Technology, 57(29): 10532–10541

[29] Sun L, Yang H, Cai Y, Li W, Liu G, Tang Y. (2019). In silico prediction of endocrine disrupting chemicals using single-label and multilabel models. Journal of Chemical Information and Modeling, 59(3): 973–982

[30] SuzukiS, Kasai K, YamauchiK (2015). Characterization of little skate (Leucoraja erinacea) recombinant transthyretin: zinc-dependent 3,3′,5-triiodo-l-thyronine binding. General and Comparative Endocrinology, 217–218: 43–53

[31] The General Office of the State Council of China (2022). China Outlines Plan to Control New Pollutants. Beijing: The State Council of China

[32] The PyMOL Molecular Graphics System (2024). Open Source PyMOL Version 2.6.0. New York: Schrödinger

[33] Trott O, Olson A J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2): 455–461

[34] Ucán-Marin F, Arukwe A, Mortensen A S, Gabrielsen G W, Letcher R J. (2010). Recombinant albumin and transthyretin transport proteins from two gull species and human: chlorinated and brominated contaminant binding and thyroid hormones. Environmental Science & Technology, 44(1): 497–504

[35] Van den Berg K J, van Raaij J A, Bragt P C, Notten W R. (1991). Interactions of halogenated industrial chemicals with transthyretin and effects on thyroid hormone levels in vivo. Archives of Toxicology, 65(1): 15–19

[36] van RossumG, the Python development team (2023). The Python Language Reference Release 3.9.16. Scotts Valley CA: CreateSpace

[37] Wang B, Sui Q, Wei H, Barcelo D, Yu G. (2023a). Bridging science, technology and policy in emerging contaminants control. Frontiers of Environmental Science & Engineering, 17(5): 65

[38] WangB, Yu G (2022). Emerging contaminant control: from science to action. Frontiers of Environmental Science & Engineering, 16(6): 81

[39] Wang Y, Jiang L, Jiang G. (2024). Emerging chemicals in China: historical development, current situation, and future outlook. Environmental Health, 2(4): 180–188

[40] Wang Y, Liu H, Yang X, Wang L. (2022). Aquatic toxicity and aquatic ecological risk assessment of wastewater-derived halogenated phenolic disinfection byproducts. Science of the Total Environment, 809: 151089

[41] Wang Z, Ma J, Wang T, Qin C, Hu X, Mosa A, Ling W. (2023b). Environmental health risks induced by interaction between phthalic acid esters (PAEs) and biological macromolecules: a review. Chemosphere, 328: 138578

[42] Wang Z, Sun H, Yao X, Li D, Xu L, Li Y, Tian S, Hou T. (2016). Comprehensive evaluation of ten docking programs on a diverse set of protein–ligand complexes: the prediction accuracy of sampling power and scoring power. Physical Chemistry Chemical Physics, 18(18): 12964–12975

[43] Wang Z, Walker G W, Muir D C G, Nagatani-Yoshida K. (2020). Toward a global understanding of chemical pollution: a first comprehensive analysis of national and regional chemical inventories. Environmental Science & Technology, 54(5): 2575–2584

[44] Weiss J M, Andersson P L, Zhang J, Simon E, Leonards P E G, Hamers T, Lamoree M H. (2015). Tracing thyroid hormone-disrupting compounds: database compilation and structure-activity evaluation for an effect-directed analysis of sediment. Analytical and Bioanalytical Chemistry, 407(19): 5625–5634

[45] Xu J, Qian Q, Xia M, Wang X, Wang H. (2021). Trichlorocarban induces developmental and immune toxicity to zebrafish (Danio rerio) by targeting TLR4/MyD88/NF-κB signaling pathway. Environmental Pollution, 273: 116479

[46] Yamauchi K. (2021). Evolution of thyroid hormone distributor proteins in fish. General and Comparative Endocrinology, 305: 113735

[47] Yamauchi K, Ishihara A, Fukazawa H, Terao Y. (2003). Competitive interactions of chlorinated phenol compounds with 3,3′,5-triiodothyronine binding to transthyretin: detection of possible thyroid-disrupting chemicals in environmental waste water. Toxicology and Applied Pharmacology, 187(2): 110–117

[48] Yang M, Zhang X. (2013). Comparative developmental toxicity of new aromatic halogenated DBPs in a chlorinated saline sewage effluent to the marine polychaete Platynereis dumerilii. Environmental Science & Technology, 47(19): 10868–10876

[49] YangX, Liu H, ChenJ (2023a). (Q)SAR models on transthyretin disrupting effects of chemicals. In: Hong H, ed. QSAR in Safety Evaluation and Risk Assessment. London: Academic Press

[50] YangX, Liu H, KuskoR, HongH (2023b). ED Profiler: machine learning tool for screening potential endocrine-disrupting chemicals. In: Hong H, ed. Machine Learning and Deep Learning in Computational Toxicology. Cham: Springer International Publishing

[51] Yang X, Lyakurwa F, Xie H, Chen J, Li X, Qiao X, Cai X. (2017). Different binding mechanisms of neutral and anionic poly-/perfluorinated chemicals to human transthyretin revealed by in silico models. Chemosphere, 182: 574–583

[52] Yang X, Ou W, Xi Y, Chen J, Liu H. (2019). Emerging polar phenolic disinfection byproducts are high-affinity human transthyretin disruptors: an in vitro and in silico study. Environmental Science & Technology, 53(12): 7019–7028

[53] Yang X, Ou W, Zhao S, Wang L, Chen J, Kusko R, Hong H, Liu H. (2021a). Human transthyretin binding affinity of halogenated thiophenols and halogenated phenols: an in vitro and in silico study. Chemosphere, 280: 130627

[54] Yang X, Ou W, Zhao S, Xi Y, Wang L, Liu H. (2021b). Rapid screening of human transthyretin disruptors through a tiered in silico approach. ACS Sustainable Chemistry & Engineering, 9(16): 5661–5672

[55] Yang X, Xie H, Chen J, Li X. (2013). Anionic phenolic compounds bind stronger with transthyretin than their neutral Forms: nonnegligible mechanisms in virtual screening of endocrine disrupting chemicals. Chemical Research in Toxicology, 26(9): 1340–1347

[56] Yap C W. (2011). PaDEL-descriptor: an open source software to calculate molecular descriptors and fingerprints. Journal of Computational Chemistry, 32(7): 1466–1474

[57] Yu Y, Wang S, Yu P, Wang D, Hu B, Zheng P, Zhang M. (2024). A bibliometric analysis of emerging contaminants (ECs) (2001−2021): Evolution of hotspots and research trends. Science of the Total Environment, 907: 168116

[58] Yu Y, Wu L. (2015). Determination and occurrence of endocrine disrupting compounds, pharmaceuticals and personal care products in fish (Morone saxatilis). Frontiers of Environmental Science & Engineering, 9(3): 475–481

[59] Yuan Y, Jia H, Xu D, Wang J. (2023). Novel method in emerging environmental contaminants detection: Fiber optic sensors based on microfluidic chips. Science of the Total Environment, 857: 159563

[60] Zhang J, Grundström C, Brännström K, Iakovleva I, Lindberg M, Olofsson A, Andersson P L, Sauer-Eriksson A E. (2018). Interspecies variation between fish and human transthyretins in their binding of thyroid-disrupting chemicals. Environmental Science & Technology, 52(20): 11865–11874

[61] Zhang J, Kamstra J H, Ghorbanzadeh M, Weiss J M, Hamers T, Andersson P L. (2015). In silico approach to identify potential thyroid hormone disruptors among currently known dust contaminants and their metabolites. Environmental Science & Technology, 49(16): 10099–10107

[62] Zhang X, Sun Y, Gao Y, Liu Z, Ding J, Zhang C, Liu W, Zhang H, Zhuang S. (2022). Thyroid dysfunction of zebrafish (Danio rerio) after early-life exposure and discontinued exposure to tetrabromobiphenyl (BB-80) and OH-BB-80. Environmental Science & Technology, 56(4): 2519–2528

[63] Zhao H, Caflisch A. (2013). Discovery of ZAP70 inhibitors by high-throughput docking into a conformation of its kinase domain generated by molecular dynamics. Bioorganic & Medicinal Chemistry Letters, 23(20): 5721–5726

[64] Zhao S, Yang X, Liu H, Xi Y, Li J. (2023). Potential disrupting effects of wastewater-derived disinfection byproducts on Chinese rare minnow (Gobiocypris rarus) transthyretin: an in vitro and in silico study. Environmental Science & Technology, 57(8): 3228–3237

[65] Zorn K M, Foil D H, Lane T R, Russo D P, Hillwalker W, Feifarek D J, Jones F, Klaren W D, Brinkman A M, Ekins S. (2020). Machine learning models for estrogen receptor bioactivity and endocrine disruption prediction. Environmental Science & Technology, 54(19): 12202–12213

Credit Author Statement

Xiangqiao Li: Investigation, Methodology, Writing - original draft. Huihui Liu: Writing - review and editing. Songshan Zhao: Investigation, Writing - original draft. Peter Watson: Writing – review and editing. Xianhai Yang: Conceptualization, Data curation, Formal analysis, Resources, Funding acquisition, Project administration, Visualization, Writing - review and editing.

Acknowledgements

The work was supported by the National Natural Science Foundation of China (No. 22176097), the Fundamental Research Funds for the Central Universities (China) (No. 30923011032).

Conflict of Interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data Availability

Data will be made available on request.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11783-024-1895-1 and is accessible for authorized users.

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