Endocrine Abstracts

The aim of the ATHENA project was to develop new test methods for detecting thyroid hormone (TH) system disruption. The primary objective of the in vivo studies was to identify new sensitive and specific neurodevelopmental endpoints that may serve as reliable indicators for such disruption. Several neurological endpoints were examined in rat offspring exposed to two thyroid peroxidase (TPO) inhibiting substances: the drug methimazole and the pesticide amitrole, followed by studies examining effects from additional substances with different modes of action. Developmental exposure to the two TPO-inhibiting substances induced a range of adverse neurodevelopmental effects, including changes in cortical gene expression, altered motor activity levels, formation of periventricular heterotopia, reduced parvalbumin-positive cells in the cortex and hippocampus, and decreased TH concentrations in the brain. These effects were consistently observed when TH concentrations in serum were reduced by 50% or more during foetal and postnatal development. By including transcriptomic analyses of the hippocampus, the project also aimed to identify candidate biomarker genes that may be more sensitive indicators of TH system disruption than the identified morphological endpoints. Exposure to chemicals affecting the TH system through other modes of action caused variable effects on TH levels. In most cases, the observed TH reductions were not substantial enough to adversely affect the newly identified TH-specific neurological endpoints, indicating that these methods may lack the sensitivity needed to protect human brain development from adverse effects caused by TH system disruptors. In light of these findings, the ATHENA consortium recommends that, in a regulatory context, changes to serum and brain TH concentrations in rodents should be recognized as predictors of adversity in their own right. Overall, the ATHENA project has provided critical insights into the impacts of TH system disruption on brain development and has suggested improved regulatory measures, for better protection of human health.