Xác định dicyclohexyl phthalate là một chất đối kháng thụ thể glucocorticoid thông qua mô phỏng phân tử và nhiều phương pháp in vitro

Springer Science and Business Media LLC - Tập 48 - Trang 3145-3154 - 2021
Yue Leng1, Yonghai Sun1, Wei Huang2, Chengyu Lv2, Jingyan Cui2, Tiezhu Li1,2, Yongjun Wang2
1College of Food Science and Engineering, Jilin University, Changchun, China
2Institute of Agro-Food Technology, Jilin Academy of Agricultural Sciences, Changchun, China

Tóm tắt

Các hoạt động tiềm năng của este phthalate (PAEs) gây ảnh hưởng đến hệ nội tiết đã được tập trung nghiên cứu gần đây. Tuy nhiên, thông tin về việc điều chỉnh thụ thể glucocorticoid (GR) của PAEs còn hạn chế. Mục tiêu của chúng tôi là đánh giá các đặc tính kích thích / đối kháng của PAEs đối với GR ở người. Phép thử gen báo cáo luciferase cho thấy các hóa chất được thử nghiệm không có tác dụng kích thích nhưng dicyclohexyl phthalate (DCHP) lại thể hiện hoạt động đối kháng theo cách đáp ứng liều trên GR trong tế bào HeLa. Tác động của DCHP đối với sự chuyển vị vào nhân của GR do dexamethasone (DEX) gây ra và biểu hiện gen của các gen nhạy cảm với glucocorticoid (G6Pase, PEPCK, FAS, GILZ và MKP-1), cũng như biểu hiện protein của G6Pase và PEPCK đã được kiểm tra thêm bằng RT-qPCR và phân tích western blot. DCHP đã đối kháng sự chuyển vị vào nhân của GR do DEX gây ra và ức chế biểu hiện gen cả trên mức mRNA và protein. Hơn nữa, kết quả từ mô phỏng docking phân tử và mô phỏng động lực học phân tử cho thấy DCHP có thể liên kết với GR và thể hiện sự điều chỉnh tiềm năng trên protein mục tiêu này. Tập hợp lại, chúng tôi cho thấy DCHP có thể hoạt động như một chất đối kháng GR in vitro và được coi là có tác động nội tiết thông qua GR ở người.

Từ khóa

#dicyclohexyl phthalate #thụ thể glucocorticoid #ươm trồng phân tử #hoạt động đối kháng #in vitro

Tài liệu tham khảo

Andrade AJM, Chahoud I (2010) Reproductive toxicity of phthalate esters. Mol Nutr Food Res 54(1):148–157 Roslev P, Vorkamp K, Aarup J, Frederiksen K, Nielsen PH (2007) Degradation of phthalate esters in an activated sludge wastewater treatment plant. Water Res 41(5):969–976 Sedha S, Gautam AK, Verma Y, Ahmad R, Kumar S (2015) Determination of in vivo estrogenic potential of di-isobutyl phthalate (DIBP) and di-isononyl phthalate (DINP) in rats. Environ Sci Pollut Res 22(22):18197–18202 Graham PR (1973) Phthalate ester plasticizers-why and how they are used. Environ Health Perspect 3:3–12 Zhang J, Li T, Zhang T, Xue P, Guan T, Yuan Y, Yu H (2017) Receptor-based fluorescence polarization assay to detect phthalate esters in Chinese spirits. Food Anal Methods 10(5):1293–1300 Zhang J, Xing X, Sun Y, Li Z, Xue P, Wang T, Li T (2016) Characterization of the binding between phthalate esters and mouse PPARα for the development of a fluorescence polarization-based competitive binding assay. Anal Methods 8(4):880–885 Das MT, Ghosh P, Thakur IS (2014) Intake estimates of phthalate esters for South Delhi population based on exposure media assessment. Environ Pollut 189:118–125 Wang X, Tao W, Xu Y, Feng J, Wang F (2014) Indoor phthalate concentration and exposure in residential and office buildings in Xi’an, China. Atmos Environ 87:146–152 Yang GCC, Yen C-H, Wang C-L (2014) Monitoring and removal of residual phthalate esters and pharmaceuticals in the drinking water of Kaohsiung City, Taiwan. J Hazard Mater 277:53–61 Le Moal J, Sharpe RM, Jorgensen N, Levine H, Jurewicz J, Mendiola J, Swan SH, Virtanen H, Christin-Maitre S, Cordier S, Toppari J, Hanke W, Network H (2016) Toward a multi-country monitoring system of reproductive health in the context of endocrine disrupting chemical exposure. Eur J Public Health 26(1):76–83 Kay VR, Bloom MS, Foster WG (2014) Reproductive and developmental effects of phthalate diesters in males. Crit Rev Toxicol 44(6):467–498 Aydoğan Ahbab M, Barlas N (2015) Influence of in utero di-n-hexyl phthalate and dicyclohexyl phthalate on fetal testicular development in rats. Toxicol Lett 233(2):125–137 Lv Y, Fang Y, Chen P, Duan Y, Huang T, Ma L, Xie L, Chen X, Chen X, Gao J, Ge R-S (2019) Dicyclohexyl phthalate blocks Leydig cell regeneration in adult rat testis. Toxicology 411:60–70 Sheikh IA (2016) Stereoselectivity and the potential endocrine disrupting activity of di-(2-ethylhexyl)phthalate (DEHP) against human progesterone receptor: a computational perspective. J Appl Toxicol 36(5):741–747 Charmandari E, Tsigos C, Chrousos G (2005) Endocrinology of the stress response. Annu Rev Physiol 67:259–284 Barnes PJ (1998) Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci 94(6):557–572 Hench PS, Kendall EC, Slocumb CH, Polley HF (1950) Effects of cortisone acetate and pituitary acth on rheumatoid arthritis, rheumatic fever and certain other conditions. Arch Intern Med 85(4):545–666 Kirwan JR, Balint G, Szebenyi B (1999) Anniversary: 50 years of glucocorticoid treatment in rheumatoid arthritis. Rheumatology 38(2):100–102 Zhang J, Zhang T, Guan T, Yu H, Li T (2017) In vitro and in silico assessment of the structure-dependent binding of bisphenol analogues to glucocorticoid receptor. Anal Bioanal Chem 409(8):2239–2246 Zhang T, Zhong S, Li T, Zhang J (2020) Saponins as modulators of nuclear receptors. Crit Rev Food Sci Nutr 60(1):94–107 Zhang T, Liang Y, Zhang J (2020) Natural and synthetic compounds as dissociated agonists of glucocorticoid receptor. Pharmacol Res 156:104802 Vandevyver S, Dejager L, Libert C (2012) On the trail of the glucocorticoid receptor: into the nucleus and back. Traffic 13(3):364–374 Lefstin JA, Yamamoto KR (1998) Allosteric effects of DNA on transcriptional regulators. Nature 392:885–888 Zhang T, Liang Y, Zuo P, Yan M, Jing S, Li T, Wang Y, Zhang J, Wei Z (2019) Identification of 20(R, S)-protopanaxadiol and 20(R, S)-protopanaxatriol for potential selective modulation of glucocorticoid receptor. Food Chem Toxicol 131:110642 Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1):55–63 Kauppi B, Jakob C, Farnegardh M, Yang J, Ahola H, Alarcon M, Calles K, Engstrom O, Harlan J, Muchmore S, Ramqvist AK, Thorell S, Ohman L, Greer J, Gustafsson JA, Carlstedt-Duke J, Carlquist M (2003) The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain—RU-486 induces a transconformation that leads to active antagonism. J Biol Chem 278(25):22748–22754 Zhang T, Zhong S, Hou L, Wang Y, Xing X, Guan T, Zhang J, Li T (2020) Computational and experimental characterization of estrogenic activities of 20(S, R)-protopanaxadiol and 20(S, R)-protopanaxatriol. J Ginseng Res 44(5):690–696 Zhang T, Zhong S, Wang Y, Dong S, Guan T, Hou L, Xing X, Zhang J, Li T (2019) In vitro and in silico perspectives on estrogenicity of tanshinones from Salvia miltiorrhiza. Food Chem 270(1):281–286 Zhang J, Li T, Wang T, Yuan C, Zhong S, Guan T, Li Z, Wang Y, Yu H, Luo Q, Wang Y, Zhang T (2018) Estrogenicity of halogenated bisphenol A: in vitro and in silico investigations. Arch Toxicol 92:1215–1223 Zhang J, Wu W, Wang Y, Xing X, Zhong S, Guan T, Zhang T, Hou L, Li T (2018) Estrogen receptor-based fluorescence polarization assay for bisphenol analogues and molecular modeling study of their complexation mechanism. Anal Chim Acta 1032(22):107–113 Sravanthi TV, Sajitha Lulu S, Vino S, Jayasri MA, Mohanapriya A, Manju SL (2017) Synthesis, docking, and evaluation of novel thiazoles for potent antidiabetic activity. Med Chem Res 26:1306–1315 Chitrala KN, Yeguvapalli S (2014) Computational prediction and analysis of breast cancer targets for 6-methyl-1,3,8-trichlorodibenzofuran. PLoS ONE 9(11):e109185 Rudel RA, Camann DE, Spengler JD, Korn LR, Brody JG (2003) Phthalates, alkylphenols, pesticides, polybrominated diphenyl ethers, and other endocrine-disrupting compounds in indoor air and dust. Environ Sci Technol 37(20):4543–4553 Sakhi AK, Lillegaard ITL, Voorspoels S, Carlsen MH, Løken EB, Brantsæter AL, Haugen M, Meltzer HM, Thomsen C (2014) Concentrations of phthalates and bisphenol A in Norwegian foods and beverages and estimated dietary exposure in adults. Environ Int 73:259–269 The Journal of Toxicological Sciencesokazaki H, Takeda S, Matsuo S, Matsumoto M, Furuta E, Kohro-Ikeda E, Aramaki H (2017) Inhibitory modulation of human estrogen receptor α and β activities by dicyclohexyl phthalate in human breast cancer cell lines. J Toxicol Sci 42(4):417–425 Sargis RM, Johnson DN, Choudhury RA, Brady MJ (2010) Environmental endocrine disruptors promote adipogenesis in the 3T3-L1 cell line through glucocorticoid receptor activation. Obesity 18(7):1283–1288 Zhang J, Zhang J, Liu R, Gan J, Liu J, Liu W (2016) Endocrine-disrupting effects of pesticides through interference with human glucocorticoid receptor. Environ Sci Technol 50(1):435–443 Gao Y, Chu S, Li J, Li J, Zhang Z, Xia C, Heng Y, Zhang M, Hu J, Wei G, Li Y, Chen N (2015) Anti-inflammatory function of ginsenoside Rg1 on alcoholic hepatitis through glucocorticoid receptor related nuclear factor-kappa B pathway. J Ethnopharmacol 173:231–240 Van Raalte DH, Ouwens DM, Diamant M (2009) Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest 39(2):81–93 Yoon J, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn C, Granner D, Newgard C, Spiegelman B (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131–138 Xu ZX, Stenzel W, Sasic SM, Smart DA, Rooney SA (1993) Glucocorticoid regulation of fatty acid synthase gene expression in fetal rat lung. Am J Physiol 265(2 Pt 1):L140–L147 Schäcke H, Rehwinkel H, Asadullah K, Cato ACB (2006) Insight into the molecular mechanisms of glucocorticoid receptor action promotes identification of novel ligands with an improved therapeutic index. Exp Dermatol 15(8):565–573 Singh N, Dalal V, Kumar P (2020) Molecular docking and simulation analysis for elucidation of toxic effects of dicyclohexyl phthalate (DCHP) in glucocorticoid receptor-mediated adipogenesis. Mol Simul 46(1):9–21