Endocrine Abstracts

Certain endocrine disrupting chemicals (EDCs) are known to disrupt the thyroid hormone system. Thyroid hormone (TH) levels are physiologically regulated by the hypothalamic–pituitary–thyroid (HPT) axis, a tight feedback loop, whereby low levels of T4 stimulate an upregulation of TSH, and conversely if T4 levels are raised. Low levels of T4 (with chronic upregulation of TSH) can lead to thyroid hyperplasia – an outcome that is recognised by regulatory groups for substances of concern to human health. In pregnant women, even acute exposure resulting in low T4 can lead to cognitive deficits in the foetus. While most chemicals disrupt the TH system by lowering T4 levels, some chemicals lower T4 but without a concomitant increase in TSH or may lower TSH as well. We were interested to investigate the different TH patterns seen after exposure to various EDCs, towards an understanding of the different mechanisms of action (MoA), we therefore conducted an extensive systematic evidence mapping exercise. We used the PECO method and included published studies that measured T4/T3 and TSH in adult rodents aged ≧ 6 weeks at the life stage of dosing. All chemical classes were included, with their exposure by gavage. Results were collated for T4/T3 and TSH measurements. We found that chemicals were mainly able to decrease T4 together with the expected increase in TSH, suggesting that the feedback loop is unaffected; although chronically unregulated levels of thyroid hormones have adverse health effects. However, some chemicals are able to decrease T4, but also decrease TSH or cause no change in TSH, thereby disrupting the feedback loop and causing apparent central hypothyroidism. EDCs can act on different molecular targets within the TH system such as transporters, enzymes and receptors in different parts of the TH system, including acting on hepatic enzymes to expedite the excretion of THs via the liver. The mechanisms by which various chemicals disrupt the TH system have not yet been fully identified for different chemical classes. Current regulatory tests for market placement of chemicals require T4 measurement, with the assumption that TSH is raised. We find that this is not the case for many chemicals and therefore the complexity of EDC MoA needs to be considered in the testing strategy in order to identify chemicals that are potentially damaging to human health.