Thyroid toxicology and brain development: should we think differently?

Thyroid hormone (TH) is essential for normal brain development. The simplicity of this statement, however, dramatically understates the complexity of the issues confronting us as we develop ways to identify factors in the environment that affect TH signaling in the developing brain, and methods of estimating the potential risk to human health of exposures to these factors. There are many known thyroid toxicants (Brucker-Davis 1998), and each has been identified solely by its ability to reduce circulating TH levels. Yet, we do not know the extent to which TH levels must decline before brain development is compromised. In addition, if there are chemicals in the environment that directly interfere with TH action on their receptors but do not affect TH levels in the blood, they cannot be identified as thyroid toxicants by the current screening methods. These two issues have been the focus of several recent reports, and the implications of their findings may change the way we think about thyroid toxicology. Few experimental studies have modeled the effect of subtle TH insufficiency on brain development, but one group has begun to investigate this issue because undiagnosed maternal hypothyroxinemia may be prevalent in the general population. Lavado-Autric et al. (2003) reported that subtle TH insufficiency in the pregnant rat disrupts the migration of neurons in the fetal cortex and hippocampus, leading to the presence of neurons in aberrant locations of the adult offspring's brain and " blurring " cortical layers. Thus, the developing brain is more sensitive to maternal TH insufficiency than originally believed. The paucity of experimental studies designed to identify the most sensitive end points of TH action in the developing brain shows that there are no well characterized end points of TH action that can be immediately recruited into toxicologic studies. However, new studies using genetic models of TH insufficiency are providing new insight that will help remedy this problem. Thyroid hormone receptors (TRs) are nuclear proteins that regulate gene expression; there are two types of TRs—α and β—and there are several isoforms of each of these two types (Zhang and Lazar 2000). These TR isoforms exhibit selective spatial and temporal patterns of expression in the developing brain, and recent work employing genetic lines carrying targeted deletions of specific TRs is revealing that specific TR isoforms mediate TH actions on specific developmental events. For example, migration of cerebellar granule cells is affected by TH acting on TRα, …