T4-mediated rescue of aortic malformations in hypothyroid rats indicates maternal thyroid status can affect great vessel development.

Pexacerfont is a corticotrophin-releasing factor subtype 1 receptor (CRF-1) antagonist developed for potential treatment of anxiety and stress-related disorders. In male rats, pexacerfont caused hepatic enzyme induction leading to increased thyroxine (T4) clearance. When administered to pregnant rats on gestation day 6 to 15, pexacerfont at 300 mg/kg/day (30× mean AUC in humans at 100 mg/day) produced similar effects on thyroid homeostasis with serum T4 and thyroid-stimulating hormone levels that were 0.3-0.5× and 3.3-3.7× of controls, respectively. At this dose, fetuses of pexacerfont-treated dams presented findings associated with maternal hypothyroidism including growth retardation and increased skeletal alterations. Additionally, there were unexpected great vessel malformations that were mostly derived from the 4th pharyngeal arch artery in 5 (4.3%) fetuses from 3 (15.8%) litters. The etiology was unclear whether the vascular malformations were related to insufficient thyroid hormones or another mechanism. To better understand this relationship, pregnant rats were implanted with a subcutaneous L-thyroxine pellet designed to provide a sustained release of T4 throughout organogenesis in rat embryos (GD 6 to 15; the dosing period of pexacerfont). T4 supplementation produced a near euthyroid state in pexacerfont-treated dams and completely prevented the fetal vascular malformations. These results suggest maternal T4 levels during organogenesis may have a role in great vessel morphogenesis associated with patterning and/or regression of pharyngeal arch arteries. Although previous clinical reports have speculated a potential relationship between thyroid hormone homeostasis and early cardiovascular development, this is the first report to experimentally demonstrate this relationship in great vessel morphogenesis.