Mode of Action: Developmental Thyroid Hormone Insufficiency—Neurological Abnormalities Resulting From Exposure to Propylthiouracil

Abstract

Because thyroid hormone is essential for normal brain development before and after birth, environmental chemicals that interfere with thyroid hormone signaling can adversely affect brain development. Adverse consequences of thyroid hormone insufficiency depend both on severity and developmental timing, indicating that environmental antithyroid factors may produce different effects at different developmental windows of exposure. Mechanistic studies can provide important insight into the potential impact of chemicals on human thyroid function, but relevance to humans must be systematically evaluated. This kind of analysis depends on data sets that include information about animals and humans. The drug 6-n-propyl-2-thiouracil (PTU) is used in animals to experimentally manipulate serum thyroid hormone levels, and in humans to treat patients, including pregnant women, with Graves' disease. A systematic analysis of the mode of action (MOA) of PTU in rats and in humans discloses similar modes of action. While the analysis predicts that PTU doses that produce thyroid hormone insufficiency in humans would adversely affect the developing brain, careful monitoring of PTU administration in pregnant and lactating humans keeps infant serum thyroid hormone levels within the normal range.

Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

“…Thyroid hormones are known to play a relevant role in brain development (Chan and Rovet, 2003;LaFranchi et al 2005), and hypothyroidism has been associated with a large number of neuroanatomical and behavioral effects (Schalock et al 1977;Haddow et al 1999;Zoeller and Crofton, 2005). Several chemicals can disrupt thyroid function leading to a decrease in thyroxine (T 4 ).…”

New Scoping Document on in vitro and ex vivo Assays for the Identification of Modulators of Thyroid Hormone Signalling

“…Several classes of environmental chemicals possess a high degree of structural similarity to THs, and thus have the potential to interfere with the binding of THs to TRs (Zoeller, 2005). For example, polychlorinated biphenyls bind to TRα and TRβ as antagonists and disrupt TR-mediated transcription.…”

“…From a clinical perspective, TPO represents a predominant autoantigen in autoimmune thyroid diseases (Czarnocka, 2011;Kaufman et al, 1989;McLachlan et al, 2007). From a toxicological perspective, chemical inhibition of TPO enzymatic activity is a well-documented molecular-initiating event in an adverse outcome pathway for thyroid hormone disruption in rodent models (Crofton, 2008;DeVito et al, 1999;Doerge et al, 2002a;Hurley, 1998;Murk et al, 2013;Zoeller et al, 2005). Treatment of hyperthyroidism with medications including methimazole (MMI) and 6-propylthiouracil (PTU) has solidified a causative relationship between TPO inhibition, decreased thyroid hormone synthesis, and subsequently decreased systemic thyroid hormone concentrations in humans and animals (Cooper, 2005;Emiliano et al, 2010;Sugawara et al, 1999;Trepanier, 2006).…”

“…However it is possible that different chemical species exerts different effects. PCBs for example may exert different actions on TRs depending on associated heterodimer partners, promoter structure, or different cofactors (Zoeller 2005).…”

“…These bioassays have traditionally been based on the quantification of a reporter enzyme and thus constitute an indirect measure of nuclear receptor activation in mammalian cells or yeasts (Zoeller, 2005; Jugan et al 2007; Moriyama et al 2002). These assays are fast and relatively simple, and yeast based assays are more cost effective and technically easier than mammalian in vitro assays.…”