A rodent thyroid-liver chip to capture thyroid toxicity on organ function level

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Diana Karwelat , Julia Kühnlenz, Thomas Steger-Hartmann, Remi Bars, Helen Tinwell, Uwe Marx, Sophie Bauer, Oliver Born, Marian Raschke
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Endocrine disruption by environmental chemicals continues to be a concern for human safety. The rat, a widely used model organism in toxicology, is very sensitive to chemical-induced thyroid perturbation, e.g., histopathological alterations in thyroid tissue. Species differences in the susceptibility to thyroid perturbation lead to uncertainty in human safety risk assessments. Hazard identification and characterization of chemically induced thyroid perturbation would therefore benefit from in vitro models addressing different mechanisms of action in a single functional assay, ideally across species. We here introduce a rat thyroid-liver chip that enables simultaneous identification of direct and indirect (liver-mediated) thyroid perturbation on organ-level functions in vitro. A second manuscript describes our work toward a human thyroid-liver chip (Kühnlenz et al., 2022). The presented microfluidic model consisting of primary rat thyroid follicles and liver 3D spheroids maintains a tissue-specific phenotype for up to 21 days. More precisely, the thyroid model exhibits a follicular architecture expressing basolateral and apical markers and secretes T4. Likewise, liver spheroids retain hepatocellular characteristics, e.g., a stable release of albumin and urea, the presence of bile canalicular networks, and the formation of T4-glucuronide. Experiments with reference chemicals demonstrated proficiency to detect direct and indirect mechanisms of thyroid perturbation through decreased thyroid hormone secretion and increased gT4 formation, respectively. Prospectively this rat thyroid-liver chip model, together with its human counterpart, may support a species-specific quantitative in vitro to in vivo extrapolation to improve a data-driven and evidence-based human safety risk assessment with significant contributions to the 3R principles.

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Karwelat, D. (2023) “A rodent thyroid-liver chip to capture thyroid toxicity on organ function level”, ALTEX - Alternatives to animal experimentation, 40(1), pp. 83–102. doi: 10.14573/altex.2108262.

Andersson, N., Arena, M., Auteri, D. et al. (2018). Guidance for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. EFSA J 16, e05311. doi:10.2903/j.efsa.2018.5311

Baker, M. (2016). Reproducibility: Respect your cells! Nature 537, 433-435. doi:10.1038/537433a

Bale, S. S., Geerts, S., Jindal, R. et al. (2016). Isolation and co-culture of rat parenchymal and non-parenchymal liver cells to evaluate cellular interactions and response. Sci Rep 6, 25329. doi:10.1038/srep25329

Barter, R. A. and Klaassen, C. D. (1992). Rat liver microsomal UDP-glucuronosyltransferase activity toward thyroxine: Characterization, induction, and form specificity. Toxicol Appl Pharmacol 115, 261-267. doi:10.1016/0041-008X(92)90331-L

Bartsch, R., Brinkmann, B., Jahnke, G. et al. (2018). Human relevance of follicular thyroid tumors in rodents caused by non-genotoxic substances. Regul Toxicol Pharmacol 98, 199-208. doi:10.1016/j.yrtph.2018.07.025

Beck-Peccoz, P., Persani, L., Calebiro, D. et al. (2006). Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis. Best Pract Res Clin Endocrinol Metab 20, 529-546. doi:10.1016/j.beem.2006.11.001

Bell, C. C., Hendriks, D. F. G., Moro, S. M. L. et al. (2016). Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. Sci Rep 6, 25187. doi:10.1038/srep25187

Berbel, P., Mestre, J. L., Santamaría, A. et al. (2009). Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: The importance of early iodine supplementation. Thyroid 19, 511-519. doi:10.1089/thy.2008.0341

Bergman, Å., Heindel, J. J., Jobling, S. et al. (2013). State of the Science of Endocrine Disrupting Chemicals 2012. World Health Organization.

Brewer, C., Yeager, N. and Cristofano, A. D. (2007). Thyroid-stimulating hormone – Initiated proliferative signals converge in vivo on the mTOR kinase without activating AKT. Cancer Res 67, 8002-8006. doi:10.1158/0008-5472.CAN-07-2471

Brucker-Davis, F. (1998). Effects of environmental synthetic chemicals on thyroid function. Thyroid 8, 827-856. doi:10.1089/thy.1998.8.827

Caballero, M. V., Ares, I., Martínez, M. et al. (2015). Fipronil induces CYP isoforms in rats. Food Chem Toxicol 83, 215-221. doi:10.1016/j.fct.2015.06.019

Capen, C. C. (1994). Mechanisms of chemical injury of thyroid gland. Prog Clin Biol Res 387, 173-191.

Carvalho, D. P. and Dupuy, C. (2017). Thyroid hormone biosynthesis and release. Mol Cell Endocrinol 458, 6-15. doi:10.1016/j.mce.2017.01.038

Chang, S.-Y., Voellinger, J. L., Van Ness, K. P. et al. (2017). Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity. Toxicol In Vitro 40, 170-183. doi:10.1016/j.tiv.2017.01.007

Cox, C. R., Lynch, S., Goldring, C. et al. (2020). Current perspective: 3D spheroid models utilizing human-based cells for investigating metabolism-dependent drug-induced liver injury. Front Med Technol 2, 611913. doi:10.3389/fmedt.2020.611913

Crivellente, F., Hart, A., Hernandez‐Jerez, A. F. et al. (2019). Establishment of cumulative assessment groups of pesticides for their effects on the thyroid. EFSA J 17, e05801. doi:10.2903/j.efsa.2019.5801

Crofton, K. M. (2008). Thyroid disrupting chemicals: Mechanisms and mixtures. Int J Androl 31, 209-223. doi:10.1111/j.1365-2605.2007.00857.x

Deisenroth, C., Soldatow, V. Y., Ford, J. et al. (2020). Development of an in vitro human thyroid microtissue model for chemical screening. Toxicol Sci 174, 63-78. doi:10.1093/toxsci/kfz238

Dellarco, V. L., McGregor, D., Berry, S. C. et al. (2006). Thiazopyr and thyroid disruption: Case study within the context of the 2006 IPCS human relevance framework for analysis of a cancer mode of action. Crit Rev Toxicol 36, 793-801. doi:10.1080/10408440600975242

Delmarcelle, A.-S., Villacorte, M., Hick, A.-C. et al. (2014). An ex vivo culture system to study thyroid development. J Vis Exp 6, e51641. doi:10.3791/51641

Denef, J.-F., Björkman, U. and Ekholm, R. (1980). Structural and functional characteristics of isolated thyroid follicles. J Ultrastruct Res 71, 185-202. doi:10.1016/S0022-5320(80)90106-9

Desai, P. K., Tseng, H. and Souza, G. R. (2017). Assembly of hepatocyte spheroids using magnetic 3D cell culture for CYP450 inhibition/induction. Int J Mol Sci 18, 1085. doi:10.3390/ijms18051085

Dybing and Sanner (1999). Consensus Report: Species differences in chemical carcinogenesis of the thyroid gland, kidney and urinary bladder. In Capen, C. C., Dybing, E., Rice, J. M. (eds), Species difference in thyroid, kidney and urinary bladder carcinogenesis. IARC Sci Publ 147, 1-14. Lyon: IARC. https://bit.ly/3gOaCU0

Dovrtelova, G., Zendulka, O., Noskova, K. et al. (2018). Effect of endocannabinoid oleamide on rat and human liver cytochrome P450 enzymes in in vitro and in vivo models. Drug Metab Dispos 46, 913-923. doi:10.1124/dmd.117.079582

ECHA – European Chemicals Agency (2017). Guidance on the application of the CLP criteria: Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures. LU: Publications Office. https://data.europa.eu/doi/10.2823/124801 (accessed 08.04.2021)

ECHA (2021). Propylthiouracil – Substance Information – ECHA. https://echa.europa.eu/de/substance-information/-/substanceinfo/100.000.095 (accessed 23.05.2021)

EU (2009). Regulation (EC) No 1107/2009 of the European Parliament and of the Council of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. OJ L 309, 1-50. http://data.europa.eu/eli/reg/2009/1107/oj

EU (2012). Regulation (EU) No 528/2012 of the European Parliament and of the Council of 22 May 2012 concerning the making available on the market and use of biocidal products. OJ L 167, 1-123. http://data.europa.eu/eli/reg/2012/528/oj

European Chemical Agency (ECHA) and European Food Safety Authority (EFSA) with the technical support of the Joint Research Centre (JRC), Andersson, N., Arena, M. et al. (2018). Guidance for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. EFSA J 16, e05311. doi:10.2903/j.efsa.2018.5311

Foster, J. R., Tinwell, H. and Melching-Kollmuss, S. (2021). A review of species differences in the control of, and response to, chemical-induced thyroid hormone perturbations leading to thyroid cancer. Arch Toxicol 95, 807-836. doi:10.1007/s00204-020-02961-6

Gärtner, R., Greil, W., Stübner, D. et al. (1985). Preparation of porcine thyroid follicles with preserved polarity: Functional and morphological properties in comparison to inside-out follicles. Mol Cell Endocrinol 40, 9-16. doi:10.1016/0303-7207(85)90152-2

Gérard, A.-C., Denef, J.-F., Colin, I. M. et al. (2004). Evidence for processing of compact insoluble thyroglobulin globules in relation with follicular cell functional activity in the human and the mouse thyroid. Eur J Endocrinol 150, 73-80. doi:10.1530/eje.0.1500073

Ghassabian, A., El Marroun, H., Peeters, R. P. et al. (2014). Downstream effects of maternal hypothyroxinemia in early pregnancy: Nonverbal IQ and brain morphology in school-age children. J Clin Endocrinol Metab 99, 2383-2390. doi:10.1210/jc.2013-4281

Gilbert, M. E., Hassan, I., Wood, C. et al. (2022). Gestational exposure to perchlorate in the rat: Thyroid hormones in fetal thyroid gland, serum, and brain. Toxicol Sci 188, 117-130. doi:10.1093/toxsci/kfac038

Haddow, J. E., Palomaki, G. E., Allan, W. C. et al. (1999). Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341, 549-555. doi:10.1056/NEJM199908193410801

Hallinger, D. R., Murr, A. S., Buckalew, A. R. et al. (2017). Development of a screening approach to detect thyroid disrupting chemicals that inhibit the human sodium iodide symporter (NIS). Toxicol Vitro 40, 66-78. doi:10.1016/j.tiv.2016.12.006

Hariparsad, N., Ramsden, D., Palamanda, J. et al. (2017). Considerations from the IQ induction working group in response to drug-drug interaction guidance from regulatory agencies: Focus on downregulation, CYP2C induction, and CYP2B6 positive control. Drug Metab Dispos 45, 1049-1059.

Hartoft-Nielsen, M., Rasmussen, Å., Feldt-Rasmussen, U. et al. (2005). Estimation of number of follicles, volume of colloid and inner follicular surface area in the thyroid gland of rats. J Anat 207, 117-124. doi:10.1111/j.1469-7580.2005.00442.x

Hassan, I., El-Masri, H., Kosian, P. A. et al. (2017). Neurodevelopment and thyroid hormone synthesis inhibition in the rat: Quantitative understanding within the adverse outcome pathway framework. Toxicol Sci 160, 57-73. doi:10.1093/toxsci/kfx163

Hassan, I., El-Masri, H., Ford, J. et al. (2020). Extrapolating in vitro screening assay data for thyroperoxidase inhibition to predict serum thyroid hormones in the rat. Toxicol Sci 173, 280-292. doi:10.1093/toxsci/kfz227

Hurley, P. M. (1998). Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environ Health Perspect 106, 437-445. doi:10.1289/ehp.98106437

Ito, O., Nakamura, Y., Tan, L. et al. (2006). Expression of cytochrome P-450 4 enzymes in the kidney and liver: Regulation by PPAR and species-difference between rat and human. Mol Cell Biochem 284, 141-148. doi:10.1007/s11010-005-9038-x

Jemnitz, K., Veres, Z., Monostory, K. et al. (2000). Glucuronidation of thyroxine in primary monolayer cultures of rat hepatocytes: In vitro induction of UDP-glucuronosyltranferases by methylcholanthrene, clofibrate, and dexamethasone alone and in combination. Drug Metab Dispos 28, 34-37.

Joannard, F., Galisteo, M., Corcos, L. et al. (2000). Regulation of phenobarbital-induction of CYP2B and CYP3A genes in rat cultured hepatocytes: Involvement of several serine/threonine protein kinases and phosphatases. Cell Biol Toxicol 16, 325-337. doi:10.1023/a:1026702615125

Jones, S. A., Moore, L. B., Shenk, J. L. et al. (2000). The pregnane X receptor: A promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14, 27-39. doi:10.1210/mend.14.1.0409

Kapałczyńska, M., Kolenda, T., Przybyła, W. et al. (2018). 2D and 3D cell cultures – A comparison of different types of cancer cell cultures. Arch Med Sci 14, 910-919. doi:10.5114/aoms.2016.63743

Khoruzhenko, A., Miot, F., Massart, C. et al. (2021). Functional model of rat thyroid follicles cultured in Matrigel. Endocr Connect 10, 570-578. doi:10.1530/EC-21-0169

Klaassen, C. D. and Hood, A. M. (2001). Effects of microsomal enzyme inducers on thyroid follicular cell proliferation and thyroid hormone metabolism. Toxicol Pathol 29, 34-40. doi:10.1080/019262301301418838

Kliewer, S. A., Moore, J. T., Wade, L. et al. (1998). An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92, 73-82. doi:10.1016/S0092-8674(00)80900-9

Kocarek, T. A., Schuetz, E. G., Strom, S. C. et al. (1995). Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit, and human hepatocytes. Drug Metab Dispos 23, 415-421.

Kooistra, L., Crawford, S., van Baar, A. L. et al. (2006). Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 117, 161-167. doi:10.1542/peds.2005-0227

Korevaar, T. I. M., Muetzel, R., Medici, M. et al. (2016). Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: A population-based prospective cohort study. Lancet Diabetes Endocrinol 4, 35-43. doi:10.1016/S2213-8587(15)00327-7

Kühnlenz, J., Karwelat, D., Steger-Hartmann, T. et al. (2022). A microfluidic thyroid-liver platform to assess chemical safety in humans. ALTEX, online ahead of print. doi:10.14573/altex.2108261

Kyffin, J. A., Sharma, P., Leedale, J. et al. (2019). Characterisation of a functional rat hepatocyte spheroid model. Toxicol In Vitro 55, 160-172. doi:10.1016/j.tiv.2018.12.014

Lee, H. B. and Blaufox, M. D. (1985). Blood volume in the rat. J Nucl Med 26, 72-76.

Levie, D., Korevaar, T. I. M., Bath, S. C. et al. (2018). Thyroid function in early pregnancy, child IQ, and autistic traits: A meta-analysis of individual participant data. J Clin Endocrinol Metab 103, 2967-2979. doi:10.1210/jc.2018-00224

Lewandowski, T. A., Seeley, M. R. and Beck, B. D. (2004). Interspecies differences in susceptibility to perturbation of thyroid homeostasis: A case study with perchlorate. Regul Toxicol Pharmacol 39, 348-362. doi:10.1016/j.yrtph.2004.03.002

Li, F., Cao, L., Parikh, S. et al. (2020). Three-dimensional spheroids with primary human liver cells and differential roles of Kupffer cells in drug-induced liver injury. J Pharm Sci 109, 1912-1923. doi:10.1016/j.xphs.2020.02.021

Li, Y., Ross-Viola, J. S., Shay, N. F. et al. (2009). Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. J Nutr 139, 898-904. doi:10.3945/jn.108.103572

Lu, C. and Di, L. (2020). In vitro and in vivo methods to assess pharmacokinetic drug-drug interactions in drug discovery and development. Biopharm Drug Dispos 41, 3-31. doi:10.1002/bdd.2212

Lu, C. and Li, A. P. (2001). Species comparison in P450 induction: Effects of dexamethasone, omeprazole, and rifampin on P450 isoforms 1A and 3A in primary cultured hepatocytes from man, Sprague-Dawley rat, minipig, and beagle dog. Chem Biol Interact 134, 271-281. doi:10.1016/s0009-2797(01)00162-4

Marty, S., Beekhuijzen, M., Charlton, A. et al. (2021). Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny – Part II: How can key events of relevant adverse outcome pathways be addressed in toxicological assessments? Crit Rev Toxicol 51, 328-358. doi:10.1080/10408444.2021.1910625

Meek, M. E. B., Bucher, J. R., Cohen, S. M. et al. (2003). A framework for human relevance analysis of information on carcinogenic modes of action. Crit Rev Toxicol 33, 591-653. doi:10.1080/713608373

Modesto, T., Tiemeier, H., Peeters, R. P. et al. (2015). Maternal mild thyroid hormone insufficiency in early pregnancy and attention-deficit / hyperactivity disorder symptoms in children. JAMA Pediatr 169, 838-845. doi:10.1001/jamapediatrics.2015.0498

Mullur, R., Liu, Y.-Y. and Brent, G. A. (2014). Thyroid hormone regulation of metabolism. Physiol Rev 94, 355-382. doi:10.1152/physrev.00030.2013

Noyes, P. D., Friedman, K. P., Browne, P. et al. (2019). Evaluating chemicals for thyroid disruption: Opportunities and challenges with in vitro testing and adverse outcome pathway approaches. Environ Health Perspect 127, 95001. doi:10.1289/EHP5297

OECD (2014). OECD Guideline for the Testing of Checmicals. 29 July 2014. Draft Proposal for a New Performance Based Test Guideline – Human cytochrome P450 (CYP) n-fold induction in vitro test method.

OECD (2018). Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption. OECD Series on Testing and Assessment, No. 150. OECD Publishing, Paris. https://www.oecd-ilibrary.org/content/publication/9789264304741-en

Oredsson, S., Coecke, S., van der Valk, J. et al. (2019). What is understood by “animal-free research”? Toxicol In Vitro 57, 143-144. doi:10.1016/j.tiv.2019.03.001

O’Shaughnessy, K. L. and Gilbert, M. E. (2020). Thyroid disrupting chemicals and developmental neurotoxicity – New tools and approaches to evaluate hormone action. Mol Cell Endocrinol 518, 110663. doi:10.1016/j.mce.2019.110663

Paul Friedman, K., Watt, E. D., Hornung, M. W. et al. (2016). Tiered high-throughput screening approach to identify thyroperoxidase inhibitors within the ToxCast Phase I and II chemical libraries. Toxicol Sci 151, 160-180. doi:10.1093/toxsci/kfw034

Paul, K. B., Hedge, J. M., Macherla, C. et al. (2013). Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat. Toxicology 312, 97-107. doi:10.1016/j.tox.2013.08.006

Paul, K. B., Hedge, J. M., Rotroff, D. M. et al. (2014). Development of a thyroperoxidase inhibition assay for high-throughput screening. Chem Res Toxicol 27, 387-399. doi:10.1021/tx400310w

Peeters, R. P. and Visser, T. J. (2000). Metabolism of thyroid hormone. In K. R. Feingold, B. Anawalt, A. Boyce et al. (eds), Thyroid Disease Manager. Chapter 5. Endotext [Internet]. South Dartmouth, MA, USA: MDText.com, Inc. http://www.ncbi.nlm.nih.gov/books/NBK285545/ (accessed 02.03.2021)

Punt, A., Bouwmeester, H., Blaauboer, B. J. et al. (2020). New approach methodologies (NAMs) for human-relevant biokinetics predictions: Meeting the paradigm shift in toxicology towards an animal-free chemical risk assessment. ALTEX 37, 607-622. doi:10.14573/altex.2003242

Raasch, M., Fritsche, E., Kurtz, A. et al. (2019). Microphysiological systems meet hiPSC technology – New tools for disease modeling of liver infections in basic research and drug development. Adv Drug Deliv Rev 140, 51-67. doi:10.1016/j.addr.2018.06.008

Ramhøj, L., Hass, U., Gilbert, M. E. et al. (2020). Evaluating thyroid hormone disruption: Investigations of long-term neurodevelopmental effects in rats after perinatal exposure to perfluorohexane sulfonate (PFHxS). Sci Rep 10, 2672. doi:10.1038/s41598-020-59354-z

Richardson, T. A. and Klaassen, C. D. (2010). Disruption of thyroid hormone homeostasis in Ugt1a-deficient Gunn rats by microsomal enzyme inducers is not due to enhanced thyroxine glucuronidation. Toxicol Appl Pharmacol 248, 38-44. doi:10.1016/j.taap.2010.07.010

Richardson, V. M., Ferguson, S. S., Sey, Y. M. et al. (2014). In vitro metabolism of thyroxine by rat and human hepatocytes. Xenobiotica 44, 391-403. doi:10.3109/00498254.2013.847990

Roques, B. B., Lacroix, M. Z., Puel, S. et al. (2012). CYP450-dependent biotransformation of the insecticide fipronil into fipronil sulfone can mediate fipronil-induced thyroid disruption in rats. Toxicol Sci 127, 29-41. doi:10.1093/toxsci/kfs094

Roques, B. B., Leghait, J., Lacroix, M. Z. et al. (2013). The nuclear receptors pregnane X receptor and constitutive androstane receptor contribute to the impact of fipronil on hepatic gene expression linked to thyroid hormone metabolism. Biochem Pharmacol 86, 997-1039. doi:10.1016/j.bcp.2013.08.012

Rousset, B., Dupuy, C., Miot, F. et al. (2000). Thyroid hormone synthesis and secretion. In K. R. Feingold, B. Anawalt, A. Boyce et al. (eds),. Thyroid Disease Manager. Chapter 2. Endotext [Internet]. South Dartmouth, MA, USA: MDText.com, Inc. http://www.ncbi.nlm.nih.gov/books/NBK285550/ (accessed 03.06.2021)

Saito, K., Kaneko, H., Sato, K. et al. (1991). Hepatic UDP-glucuronyltransferase(s) activity toward thyroid hormones in rats: Induction and effects on serum thyroid hormone levels following treatment with various enzyme inducers. Toxicol Appl Pharmacol 111, 99-106. doi:10.1016/0041-008X(91)90138-5

Saito, Y., Onishi, N., Takami, H. et al. (2018). Development of a functional thyroid model based on an organoid culture system. Biochem Biophys Res Commun 497, 783-789. doi:10.1016/j.bbrc.2018.02.154

Samimi, H., Atlasi, R., Parichehreh-Dizaji, S. et al. (2021). A systematic review on thyroid organoid models: Time-trend and its achievements. Am J Physiol-Endocrinol Metab 320, E581-E590. doi:10.1152/ajpendo.00479.2020

Santini, F., Vitti, P., Ceccarini, G. et al. (2003). In vitro assay of thyroid disruptors affecting TSH-stimulated adenylate cyclase activity. J Endocrinol Invest 26, 950-955. doi:10.1007/BF03348190

Schröder-van der Elst, J. P., van der Heide, D., Romijn, J. A. et al. (2004). Differential effects of natural flavonoids on growth and iodide content in a human Na+/I- symporter-transfected follicular thyroid carcinoma cell line. Eur J Endocrinol 150, 557-564. doi:10.1530/eje.0.1500557

Singh, G. and Correa, R. (2021). Methimazole. In StatPearls. Treasure Island, FL, USA: StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK545223/ (accessed 23.05.2021)

Sutcliffe, C. and Harvey, P. W. (2015). Chapter 11 – Endocrine disruption of thyroid function: Chemicals, mechanisms, and toxicopathology. In P. D. Darbre (ed.), Endocrine Disruption and Human Health (201-217). Boston, USA: Academic Press. doi:10.1016/B978-0-12-801139-3.00011-9

Vansell, N. R. and Klaassen, C. D. (2002). Increase in rat liver UDP-glucuronosyltransferase mRNA by microsomal enzyme inducers that enhance thyroid hormone glucuronidation. Drug Metab Dispos 30, 240-246. doi:10.1124/dmd.30.3.240

Vansell, N. R., Muppidi, J. R., Habeebu, S. M. et al. (2004). Promotion of thyroid tumors in rats by pregnenolone-16α-carbonitrile (PCN) and polychlorinated biphenyl (PCB). Toxicol Sci 81, 50-59. doi:10.1093/toxsci/kfh197

Viollon-Abadie, C., Lassere, D., Debruyne, E. et al. (1999). Phenobarbital, β-naphthoflavone, clofibrate, and pregnenolone-16α-carbonitrile do not affect hepatic thyroid hormone UDP-glucuronosyl transferase activity, and thyroid gland function in mice. Toxicol Appl Pharmacol 155, 1-12. doi:10.1006/taap.1998.8558

Wang, J., Hallinger, D. R., Murr, A. S. et al. (2018). High-throughput screening and quantitative chemical ranking for sodium-iodide symporter inhibitors in ToxCast phase I chemical library. Environ Sci Technol 52, 5417-5426. doi:10.1021/acs.est.7b06145

Wikswo, J. P. (2014). The relevance and potential roles of microphysiological systems in biology and medicine. Exp Biol Med (Maywood) 239, 1061-1072. doi:10.1177/1535370214542068

Zoeller, R. T., Tan, S. W. and Tyl, R. W. (2007). General background on the hypothalamic-pituitary-thyroid (HPT) axis. Crit Rev Toxicol 37, 11-53. doi:10.1080/10408440601123446

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