Thyroid system-disrupting chemicals: interference with thyroid hormone binding to plasma proteins and the cellular thyroid hormone signaling pathway

In vertebrates, thyroid hormones are essential for post-embryonic development, such as establishing the central nervous system in mammals and metamorphosis in amphibians. The present paper summarizes the possible extra-thyroidal processes that environmental chemicals are known to or suspected to target in the thyroid hormone-signaling pathway. We describe how such chemicals interfere with thyroid-hormone-binding protein functions in plasma, thyroid-hormone-uptake system, thyroid-hormone-metabolizing enzymes, and activation or suppression of thyroid-hormone-responsive genes through thyroid-hormone receptors in mammals and amphibian tadpoles. Several organohalogens affect different aspects of the extra-thyroidal thyroid-hormone-signaling pathway but hardly affect thyroid hormone binding to receptors. Rodents and amphibian tadpoles are most sensitive to the effects of environmental chemicals during specific thyroid-hormone-related developmental windows. Possible mechanisms by which environmental chemicals exert multipotent activities beyond one hormone-signaling pathway are discussed.