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Evaluating Endocrine Disruption In Vitro

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In Vitro Toxicology Systems

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

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Abstract

This chapter describes the relevant physiology and anatomy of endocrine organs most often targeted by xenobiotics and the strategies and in vitro models in current use that have proven important for studying endocrine disruption. This chapter focuses on the reproductive system, the adrenal gland, and the thyroid. Detailed methodology is not described in this chapter, but rather practical considerations for the available methods are described and resources referenced to direct readers to further details of each assay. An understanding of the regulatory processes and function of the endocrine glands is critical in order to properly utilize the appropriate in vitro models to screen compounds or perform investigative studies and be able to interpret results. Antiestrogenic or estrogenic actions of xenobiotics have been a main concern for the field of endocrine disruption. Common endpoints used to study such effects include estrogen receptor (ER) binding, proliferation of estrogen-responsive cells, and ER-dependent reporter gene activity in multiple cell types. Inhibition of steroidogenesis is a primary mechanism of endocrine disruption, and chemical-induced alterations in biosynthesis of both reproductive and adrenal steroids can be tested in the human H295R adrenocortical cell line. For adrenal gland dysfunction, differentiating stress from direct or indirect actions on adrenals is important. If signs of stress are not observed in vivo, evidence from H295R cells or primary adrenocortical cell models can often identify direct effects on adrenals. Endpoints can include cytotoxicity, lipid accumulation, changes in protein or gene expression, altered signaling of key pathways, or changes in steroid synthesis in response physiologic signals. Typical alterations in thyroid function are cell proliferation or thyroid hormone synthesis. The latter can be disrupted by inhibition of thyroperoxidase or iodide uptake or by upregulation of hepatic thyroid hormone-inactivating enzymes, which is typically rat specific. In vitro assays include microsomal thyroperoxidase activity assays and cellular assays for iodide uptake in FRTL-5 or PCC13 rat thyroid cell lines. More in-depth investigations on alterations in signaling pathways, for example, can utilize FRTL-5 or PCC13 cells, or primary cells from multiple species, including human, dog, rodent, pig, or cow thyroid cells. Overall, many in vitro models are available to test for endocrine disruption, but many remain to be properly validated, and caveats exist for most. In spite of this, in vitro models have proven to be essential for both screening purposes and mechanistic investigations.

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Acknowledgements

I would like to thank Katie Kubek, Maria Magnifico, and Amy Erickson for their support in writing this chapter, both in terms of doing the laboratory work described here and for the intellectual input that they provided.

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  1. Novartis Institutes for BioMedical Research Inc., 300 Technology Square, Cambridge, MA, 02081, USA

    Patrick J. Devine

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  1. European Commission Joint Research Centre, Ispra, Varese, Italy

    Anna Bal-Price

  2. Innsbruck Medical University, Innsbruck, Austria

    Paul Jennings

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Devine, P.J. (2014). Evaluating Endocrine Disruption In Vitro. In: Bal-Price, A., Jennings, P. (eds) In Vitro Toxicology Systems. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0521-8_13

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  • DOI: https://doi.org/10.1007/978-1-4939-0521-8_13

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