Inhibition of the thyroid hormone pathway in Xenopus laevis by 2-mercaptobenzothiazole

Determining the effects of chemicals on the thyroid system is an important aspect of evaluating chemical safety from an endocrine disrupter perspective. Since there are numerous chemicals to test and limited resources, prioritizing chemicals for subsequent in vivo testing is critical. 2-Mercaptobenzothiazole (MBT), a high production volume chemical, was tested and shown to inhibit thyroid peroxidase (TPO) enzyme activity in vitro, a key enzyme necessary for the synthesis of thyroid hormone. To determine the thyroid disrupting activity of MBT in vivo, Xenopus laevis larvae were exposed using 7- and 21-day protocols. The 7-day protocol used 18–357 μg/L MBT concentrations and evaluated: metamorphic development, thyroid histology, circulating T4, circulating thyroid stimulating hormone, thyroidal sodium-iodide symporter gene expression, and thyroidal T4, T3, and related iodo-amino acids. The 21-day protocol used 23–435 μg/L MBT concentrations and evaluated metamorphic development and thyroid histology. Both protocols demonstrated that MBT is a thyroid disrupting chemical at the lowest concentrations tested. These studies complement the in vitro study used to identify MBT as a high priority for in vivo testing, supporting the utility/predictive potential of a tiered approach to testing chemicals for TPO activity inhibition. The 7-day study, with more comprehensive, sensitive, and diagnostic endpoints, provides information at intermediate biological levels that enables linking various endpoints in a robust and integrated pathway for thyroid hormone disruption associated with TPO inhibition.

► 2-Mercaptobenzothiazole (MBT) was identified in vitro as a novel inhibitor of thyroid peroxidase, a key enzyme in thyroid hormone synthesis.
► MBT was shown to disrupt normal thyroid function in amphibians at aqueous concentrations in the low μg/L range.
► A variety of endpoints from different biological levels responded consistently, establishing linkages among the endpoints.
► NIS gene expression appears to be a robust and sensitive endpoint that could be used as an indicator of HPT compensation.
► Discordant results among mammalian and amphibian studies suggest that factors determining sensitivity need to be addressed.