A microfluidic thyroid-liver platform to assess chemical safety in humans

Main Article Content

Julia Kühnlenz
Diana Karwelat
Thomas Steger-Hartmann
Marian Raschke
Sophie Bauer
Özlem Vural
Uwe Marx
Helen Tinwell
Remi Bars

Abstract

Thyroid hormones (THs) are crucial regulators of human metabolism and early development. During the safety assessment of plant protection products, the human relevance of chemically induced TH perturbations observed in test animals remains uncertain. European regulatory authorities request follow-up in vitro studies to elucidate human-relevant interferences of thyroid gland function, or TH catabolism through hepatic enzyme induction. However, human in vitro assays, based on single molecular initiating events, poorly reflect the complex TH biology and related liver-thyroid axis. To address this complexity, we present human three-dimensional thyroid and liver organoids with key functions of TH metabolism. The thyroid model resembled in vivo-like follicular architecture and a TSH-dependent triiodothyronine synthesis over 21 days which was inhibited by methimazole. The HepaRG-based liver model, secreting critical TH-binding proteins albumin and thyroxine-binding globulin (TBG), emulated an active TH catabolism via the formation of glucuronidated and sulfated thyroxine (gT4/sT4). Activation of the nuclear receptors PXR and AHR was demonstrated via the induction of specific CYP isoenzymes by rifampicin, pregnenolone-16a-carbonitrile and β-naphthoflavone. However, this nuclear receptor activation, assumed to regulate UDP-glucuronosyltransferases and sulfotransferases, appeared to have no effect on gT4 and sT4 formation in this human-derived hepatic cell line model. Finally established single-tissue models were successfully co-cultured in a perfused two-organ chip for 21 days. In conclusion, this model presents a first step towards a complex multimodular human platform, which will help to identify both direct and indirect thyroid disruptors that are relevant from a human safety perspective.

Article Details

How to Cite
Kühnlenz, J., Karwelat, D., Steger-Hartmann, T., Raschke, M., Bauer, S., Vural, Özlem, Marx, U., Tinwell, H. and Bars, R. (2022) “A microfluidic thyroid-liver platform to assess chemical safety in humans”, ALTEX - Alternatives to animal experimentation. doi: 10.14573/altex.2108261.
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References

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