In vitro and in silico approach to study the hormonal activities of the alternative plasticizer tri-(2-ethylhexyl) trimellitate TEHTM and its metabolites.

Benzoates / metabolism Cell Line, Tumor Computer Simulation Endocrine Disruptors / metabolism Estradiol / metabolism Humans Molecular Docking Simulation Plasticizers / metabolism Receptors, Androgen / drug effects Receptors, Estrogen / drug effects Receptors, Thyroid Hormone / drug effects Testosterone / metabolism
In silico Medical devices Steroidogenesis T-screen assay TEHTM hER and hAR reporter gene assays

Journal

Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615

Informations de publication

Date de publication:
03 2022
Historique:
received: 17 08 2021
accepted: 12 01 2022
pubmed: 29 1 2022
medline: 30 3 2022
entrez: 28 1 2022
Statut: ppublish

Résumé

Tri-(2-ethylhexyl) trimellitate (TEHTM) is a plasticizer for polyvinyl chloride (PVC) material used in medical devices. It is an alternative to di-(2-ethylhexyl) phthalate (DEHP), a well-known reprotoxic and endocrine disruptor. As plasticizers are known to easily migrate when in contact with fatty biological fluids, patient exposure to TEHTM is highly probable. However, there is currently no data on the potential endocrine-disrupting effects of its human metabolites. To evaluate the effects of TEHTM metabolites on endocrine activity, they were first synthesized and their effects on estrogen, androgen and thyroid receptors, as well as steroid synthesis, were investigated by combining in vitro and in silico approaches. Among the primary metabolites, only 4-MEHTM (4-mono-(2-ethylhexyl) trimellitate) showed agonist activities on ERs and TRs, while three diesters were TR antagonists at non-cytotoxic concentrations. These results were completed by docking experiments which specified the ER and TR isoforms involved. A mixture of 2/1-MEHTM significantly increased the estradiol level and reduced the testosterone level in H295R cell culture supernatants. The oxidized secondary metabolites of TEHTM had no effect on ER, AR, TR receptors or on steroid hormone synthesis. Among the fourteen metabolites, these data showed that two of them (4-MEHTM and 2/1-MEHTM) induced effect on hormonal activities in vitro. However, by comparing the concentrations of the primary metabolites found in human urine with the active concentrations determined in bioassays, it can be suggested that the metabolites will not be active with regard to estrogen, androgen, thyroid receptors and steroidogenesis-mediated effects.

Identifiants

DOI: 10.1007/s00204-022-03230-4 PMID: 35089383
pubmed: 35089383
doi: 10.1007/s00204-022-03230-4
pii: 10.1007/s00204-022-03230-4
doi:

Substances chimiques

Benzoates 0
Endocrine Disruptors 0
Plasticizers 0
Receptors, Androgen 0
Receptors, Estrogen 0
Receptors, Thyroid Hormone 0
tri-(2-ethylhexyl)trimellitate 3319-31-1
Testosterone 3XMK78S47O
Estradiol 4TI98Z838E

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

899-918

Informations de copyright

© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Références

Bernard L, Cueff R, Breysse C, Décaudin B, Sautou V (2015) Migrability of PVC plasticizers from medical devices into a simulant of infused solutions. Int J Pharm 485(1–2):341–347. https://doi.org/10.1016/j.ijpharm.2015.03.030
doi: 10.1016/j.ijpharm.2015.03.030 pubmed: 25796128
Bui TT, Giovanoulis G, Cousins AP, Magnér J, Cousins IT, de Wit CA (2016) Human exposure, hazard and risk of alternative plasticizers to phthalate esters. Sci Total Environ 541(janvier):451–467. https://doi.org/10.1016/j.scitotenv.2015.09.036
doi: 10.1016/j.scitotenv.2015.09.036 pubmed: 26410720
de Jésus-Tran P, Karine P-L, Cantin L, Blanchet J, Labrie F, Breton R (2006) Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity. Protein Sci 15(5):987–999. https://doi.org/10.1110/ps.051905906
doi: 10.1110/ps.051905906
Desdoits-Lethimonier C, Albert O, Le Bizec B, Perdu E, Zalko D, Courant F, Lesne L, Guille F, Dejucq-Rainsford N, Jegou B (2012) Human testis steroidogenesis is inhibited by phthalates. Hum Reprod 27(5):1451–1459. https://doi.org/10.1093/humrep/des069
doi: 10.1093/humrep/des069 pubmed: 22402212
Dow RL, Steven RS, Ernest SP, Richard FH, Phoebe C, Peter C, Eunsun L et al. 2003. Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TR_ subtype-selective thyromimetics. Bioorg Med Chem Lett 4
Dykstra KD, Liangqin G, Elizabeth TB, Wanda C, Yi TY, Edward CH, Carolyn AD et al (2007) Estrogen receptor ligands. Part 16: 2-aryl indoles as highly subtype selective ligands for ERα. Bioorg Med Chem Lett 17(8):2322–2328. https://doi.org/10.1016/j.bmcl.2007.01.054
doi: 10.1016/j.bmcl.2007.01.054 pubmed: 17289385
ECHA (2021) Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate—substance information—ECHA. 2021. https://echa.europa.eu/fr/substance-information/-/substanceinfo/100.020.019
Eckert E, Johannes M, Thomas G (2015) Simultaneous determination of polyvinylchloride plasticizers di(2-ethylhexyl) phthalate and tri(2-ethylhexyl) trimellitate and its degradation products in blood by liquid chromatography–tandem mass spectrometry. J Chromatogr A 1410(septembre):173–180. https://doi.org/10.1016/j.chroma.2015.07.083
doi: 10.1016/j.chroma.2015.07.083 pubmed: 26243703
Eckert E, Frank M, Thomas G, Ariawan P, Johannes M, Robert C (2016) Comparative study on the migration of di-2-ethylhexyl phthalate (DEHP) and tri-2-ethylhexyl trimellitate (TOTM) into blood from PVC tubing material of a heart-lung machine. Chemosphere 145(fevrier):10–16. https://doi.org/10.1016/j.chemosphere.2015.11.067
doi: 10.1016/j.chemosphere.2015.11.067 pubmed: 26650574
Eckert E, Johannes M, Christine H, Ariawan P, Robert C, Thomas G, Frank M (2020) Plasticizer exposure of infants during cardiac surgery. Toxicol Lett 330(septembre):7–13. https://doi.org/10.1016/j.toxlet.2020.04.004
doi: 10.1016/j.toxlet.2020.04.004 pubmed: 32387387
Eljezi T, Pierre P, Damien R, Jérémy P, Jean-Michel C, Marie-Christine C, Valérie S, Gaël G, Emmanuel M (2017) In vitro cytotoxic effects of DEHP-alternative plasticizers and their primary metabolites on a L929 cell line. Chemosphere 173(avril):452–459. https://doi.org/10.1016/j.chemosphere.2017.01.026
doi: 10.1016/j.chemosphere.2017.01.026 pubmed: 28129623
Ermler S, Scholze M, Kortenkamp A (2010) The sensitivity of the MDA-Kb2 cell in vitro assay in detecting anti-androgenic chemicals—identification of sources of variability and estimation of statistical power. Toxicol in Vitro 24(6):1845–1853. https://doi.org/10.1016/j.tiv.2010.05.007
doi: 10.1016/j.tiv.2010.05.007 pubmed: 20488240
EU 1272/2008. s. d. Regulation (EU) 1272/2008 of the European parliament and of the council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation EC No 690 1907/2006
Hahn C-G, Pawlyk AC, Whybrow PC, Tejani-Butt SM (1999) Differential expression of thyroid hormone receptor isoforms by thyroid hormone and lithium in rat GH3 and B103 cells. Biol Psychiatr 45(8):1004–1012. https://doi.org/10.1016/S0006-3223(98)00164-4
doi: 10.1016/S0006-3223(98)00164-4
Hecker M, Newsted JL, Murphy MB, Higley EB, Jones PD, Rudolf Wu, Giesy JP (2006) Human adrenocarcinoma (H295R) cells for rapid in vitro determination of effects on steroidogenesis: hormone production. Toxicol Appl Pharmacol 217(1):114–124. https://doi.org/10.1016/j.taap.2006.07.007
doi: 10.1016/j.taap.2006.07.007 pubmed: 16962624
Höllerer C, Becker G, Göen T, Eckert E (2018a) Human metabolism and kinetics of tri-(2-ethylhexyl) trimellitate (TEHTM) after oral administration. Arch Toxicol 92(9):2793–2807. https://doi.org/10.1007/s00204-018-2264-2
doi: 10.1007/s00204-018-2264-2 pubmed: 30027468
Höllerer C, Göen T, Eckert E (2018b) Comprehensive monitoring of specific metabolites of tri-(2-ethylhexyl) trimellitate (TEHTM) in urine by column-switching liquid chromatography–tandem mass spectrometry. Anal Bioanal Chem 410(18):4343–4357. https://doi.org/10.1007/s00216-018-1086-7
doi: 10.1007/s00216-018-1086-7 pubmed: 29687250
Iwase H (2014) Biological effects of the plasticizer tris (2-ethylhexyl) trimellitate. Clin Pharmacol Biopharm. https://doi.org/10.4172/2167-065X.S2-004
doi: 10.4172/2167-065X.S2-004
Kambia K, Dine T, Azar R, Gressier B, Luyckx M, Brunet C (2001) Comparative study of the leachability of di(2-ethylhexyl) phthalate and tri(2-ethylhexyl) trimellitate from haemodialysis tubing. Int J Pharm 229(1–2):139–146. https://doi.org/10.1016/S0378-5173(01)00840-7
doi: 10.1016/S0378-5173(01)00840-7 pubmed: 11604266
Kambia N, Dine T, Gressier B, Dupin-Spriet T, Luyckx M, Brunet C (2004) Evaluation of the direct toxicity of trioctyltrimellitate (TOTM), di(2-ethylhexyl) phthalate (DEHP) and their hydrolysis products on isolated rat hepatocytes. Int J Artif Organs 27(11):971–978. https://doi.org/10.1177/039139880402701110
doi: 10.1177/039139880402701110 pubmed: 15636055
Kambia NK, Séverin I, Farce A, Moreau E, Dahbi L, Duval C, Dine T, Sautou V, Chagnon M-C (2019) In vitro and in silico hormonal activity studies of di-(2-ethylhexyl)terephthalate, a di-(2-ethylhexyl)phthalate substitute used in medical devices, and its metabolites. J Appl Toxicol 39(7):1043–1056. https://doi.org/10.1002/jat.3792
doi: 10.1002/jat.3792 pubmed: 30847963
Kambia N, Isabelle S, Amaury F, Laurence D, Thierry D, Emmanuel M, Valérie S, Marie-Christine C (2021) Comparative effects of di-(2-ethylhexyl)phthalate and di-(2-ethylhexyl)terephthalate metabolites on thyroid receptors: in vitro and in silico studies. Metabolites 11(2):94. https://doi.org/10.3390/metabo11020094
doi: 10.3390/metabo11020094 pubmed: 33578748 pmcid: 7916494
Koch HM, Preuss R, Angerer J (2006) Di(2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure—an update and latest results1. Int J Androl 29(1):155–165. https://doi.org/10.1111/j.1365-2605.2005.00607.x
doi: 10.1111/j.1365-2605.2005.00607.x pubmed: 16466535
Kuhlmann L, Thomas G, Elisabeth E (2021) Sensitive monitoring of the main metabolites of tri-(2-ethylhexyl) trimellitate (TOTM) in urine by coupling of on-line SPE, UHPLC and tandem mass spectrometry. J Chromatogr B 1171(mai):122618. https://doi.org/10.1016/j.jchromb.2021.122618
doi: 10.1016/j.jchromb.2021.122618
Lovekamp TN, Davis BJ (2001) Mono-(2-ethylhexyl) phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells. Toxicol Appl Pharmacol 172(3):217–224. https://doi.org/10.1006/taap.2001.9156
doi: 10.1006/taap.2001.9156 pubmed: 11312650
Maglich JM, Max K, Robert EC, Mathew TP (2014) More than just hormones: H295R cells as predictors of reproductive toxicity. Reprod Toxicol 45(juin):77–86. https://doi.org/10.1016/j.reprotox.2013.12.009
doi: 10.1016/j.reprotox.2013.12.009 pubmed: 24434083
Moche H, Aouatif C, Sergio N, Jean-Marc C, Fabrice N (2021) Comparison of in vitro endocrine activity of phthalates and alternative plasticizers. Édité par You-Cheng Hseu. J Toxicol 2021(fevrier):1–14. https://doi.org/10.1155/2021/8815202
doi: 10.1155/2021/8815202
Münch F, Christine H, André K, Elisabeth E, André R, Robert C, Thomas G (2018) Effect of phospholipid coating on the migration of plasticizers from PVC tubes. Chemosphere 202(juillet):742–749. https://doi.org/10.1016/j.chemosphere.2018.03.136
doi: 10.1016/j.chemosphere.2018.03.136 pubmed: 29604561
Murawski A, Maria IHS-T, Enrico R, Christoph S, Katja K, Gabriele L, Elisabeth E et al (2021) Metabolites of 4-methylbenzylidene camphor (4-MBC), butylated hydroxytoluene (BHT), and tris(2-ethylhexyl) trimellitate (TOTM) in urine of children and adolescents in Germany—human biomonitoring results of the German environmental survey GerES V (2014–2017). Environ Res 192(janvier):110345. https://doi.org/10.1016/j.envres.2020.110345
doi: 10.1016/j.envres.2020.110345 pubmed: 33096061
Norman MF, Lavin TN (1989) Antagonism of thyroid hormone action by amiodarone in rat pituitary tumor cells. J Clin Investig 83(1):306–313. https://doi.org/10.1172/JCI113874
doi: 10.1172/JCI113874 pubmed: 2910914 pmcid: 303675
OECD (2018) Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption. OECD Series on Testing and Assessment. OECD. https://doi.org/10.1787/9789264304741-en
OECD test guideline 456 (2011) Test No. 456: H295R steroidogenesis assay. OECD guidelines for the testing of chemicals, Section 4. OECD. https://doi.org/10.1787/9789264122642-en .
OECD test guideline 455 (2016) OECD Test No. 455: the stably transfected human estrogen receptor-alpha transcriptional activation assay for detection of estrogenic agonist-activity of chemicals | en |. 2016. https://www.oecd.org/publications/test-no-455-the-stably-transfected-human-estrogen-receptor-alpha-transcriptional-activation-assay-for-detection-of-estrogenic-9789264076372-en.htm
OECD test guideline 458 (2020) Test No. 458: stably transfected human androgen receptor transcriptional activation assay for detection of androgenic agonist and antagonist activity of chemicals. OECD Guidelines for the Testing of Chemicals, Section 4. OECD. https://doi.org/10.1787/9789264264366-en
Ohashi A, Kotera H, Hori H, Hibiya M, Watanabe K, Murakami K, Hasegawa M, Tomita M, Hiki Y, Sugiyama S (2005) Evaluation of endocrine disrupting activity of plasticizers in polyvinyl chloride tubes by estrogen receptor alpha binding assay. J Artif Organs 8(4):252. https://doi.org/10.1007/s10047-005-0307-y
doi: 10.1007/s10047-005-0307-y pubmed: 16362523
Pinguet J, Nicolas K, Teuta E, Céline L, Emmanuel M, Lise B, Benoit B et al (2019) New SPE–LC–MS/MS method for the simultaneous determination in urine of 22 metabolites of DEHP and alternative plasticizers from PVC medical devices. Talanta 198(juin):377–389. https://doi.org/10.1016/j.talanta.2019.01.115
doi: 10.1016/j.talanta.2019.01.115 pubmed: 30876575
Radke EG, Joseph MB, John DM, Glinda SC (2018) Phthalate exposure and male reproductive outcomes: a systematic review of the human epidemiological evidence. Environ Int 121(decembre):764–793. https://doi.org/10.1016/j.envint.2018.07.029
doi: 10.1016/j.envint.2018.07.029 pubmed: 30336412
Schriks M, Vrabie CM, Gutleb AC, Faassen EJ, Rietjens IMCM, Murk AJ (2006) T-screen to quantify functional potentiating, antagonistic and thyroid hormone-like activities of poly halogenated aromatic hydrocarbons (PHAHs). Toxicol in Vitro 20(4):490–498. https://doi.org/10.1016/j.tiv.2005.09.001
doi: 10.1016/j.tiv.2005.09.001 pubmed: 16219445
Silva MJ, Samandar E, Preau JL, Needham LL, Calafat AM (2006) Urinary oxidative metabolites of di(2-ethylhexyl) phthalate in humans. Toxicology 219(1–3):22–32. https://doi.org/10.1016/j.tox.2005.10.018
doi: 10.1016/j.tox.2005.10.018 pubmed: 16332407
Sirbasku DA, Rajbabu P, Hidetaka S, John EE (1991) Thyroid hormone-dependent pituitary tumor cell growth in serum-free chemically defined culture. A new regulatory role for apotransferrin. Biochemistry 30(30):7466–7477. https://doi.org/10.1021/bi00244a015
doi: 10.1021/bi00244a015 pubmed: 1854748
Souza PCT, Puhl AC, Martínez L, Aparício R, Nascimento AS, Figueira ACM, Nguyen P, Webb P, Skaf MS, Polikarpov I (2014) Identification of a new hormone-binding site on the surface of thyroid hormone receptor. Mol Endocrinol 28(4):534–545. https://doi.org/10.1210/me.2013-1359
doi: 10.1210/me.2013-1359 pubmed: 24552590 pmcid: 5414925
Testai E, Philippe H, Suresh CR, Ulrike B, Aldert P, Wim DJ et al (2016) The safety of medical devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update). Regul Toxicol Pharmacol RTP 76(avril):209–210. https://doi.org/10.1016/j.yrtph.2016.01.013
doi: 10.1016/j.yrtph.2016.01.013 pubmed: 26854686
Thomas RS, Richard SP, Anton S, Suzanne CF, Kevin MC, Warren MC, Donna LM (2018) The US federal Tox21 program: a strategic and operational plan for continued leadership. ALTEX Altern Anim Exp 35(2):163–168. https://doi.org/10.14573/altex.1803011
doi: 10.14573/altex.1803011
Van Vliet EDS, Reitano EM, Chhabra JS, Bergen GP, Whyatt RM (2011) A review of alternatives to di (2-ethylhexyl) phthalate-containing medical devices in the neonatal intensive care unit. J Perinatol 31(8):551–560. https://doi.org/10.1038/jp.2010.208
doi: 10.1038/jp.2010.208 pubmed: 21311501 pmcid: 3377474
Wilson VS (2002) A novel cell line, MDA-Kb2, that stably expresses an androgen- and glucocorticoid-responsive reporter for the detection of hormone receptor agonists and antagonists. Toxicol Sci 66(1):69–81. https://doi.org/10.1093/toxsci/66.1.69
doi: 10.1093/toxsci/66.1.69 pubmed: 11861974

Auteurs

Laurence Dahbi (L)

Derttech "Packtox", NUTOX, INSERM U1231, Université Bourgogne Franche-Comté, 21000, Dijon, France.

Amaury Farce (A)

Université de Lille, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, 59000, Lille, France.

Nicolas Kambia (N)

Université de Lille, CHU Lille, ULR 7365 GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, 59000, Lille, France.

Isabelle Séverin (I)

Derttech "Packtox", NUTOX, INSERM U1231, Université Bourgogne Franche-Comté, 21000, Dijon, France.

Thierry Dine (T)

Université de Lille, CHU Lille, ULR 7365 GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, 59000, Lille, France.

Emmanuel Moreau (E)

Université Clermont Auvergne, INSERM U1240, Imagerie Moléculaire et Stratégies Théranostiques, 63000, Clermont-Ferrand, France.

Valérie Sautou (V)

Université Clermont Auvergne, CHU Clermont Ferrand, Clermont Auvergne INP, CNRS, ICCF, 63000, Clermont-Ferrand, France.

Marie-Christine Chagnon (MC)

Derttech "Packtox", NUTOX, INSERM U1231, Université Bourgogne Franche-Comté, 21000, Dijon, France. Marie-Christine.Chagnon@u-bourgogne.fr.
ORCID: 0000-0003-1275-657X

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Classifications MeSH

Recherchemedicale.com › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Benzoates › In vitro and in silico approach to study the...
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Recherchemedicale.com › Actions chimiques et utilisations › Actions toxiques › Perturbateurs endocriniens › In vitro and in silico approach to study the...
Recherchemedicale.com › Hormones gonadiques › Hormones sexuelles stéroïdiennes › Congénères de l'oestradiol › Oestradiol › In vitro and in silico approach to study the...
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Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs des hormones thyroïdiennes › In vitro and in silico approach to study the...
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