TRANSIENT PERINATAL HYPERTHYROIDISM IN MCT8 DEFICIENT MICE

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 414-436-HPT Axis Biology & Action
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-429
Alfonso Massimilano Ferrara*1, Xiao Hui Liao1, Pilar Gil-Ibáñez2, Juan Bernal2, Roy E Weiss1, Alexandra M Dumitrescu1 and Samuel Refetoff1
1University of Chicago, Chicago, IL, 2CSIC, Madrid, Spain
The active thyroid hormones (TH), T3 and its precursor, T4 are essential for mammalian development. Most TH actions result from changes in gene expression mediated by the binding of T3 to TH receptors. Therefore, the maintenance of the proper intracellular T3 concentration is fundamental. For this, TH cell membrane transporters are important for the provision of intracellular T3.

The importance of transporters for TH action is illustrated by the severe phenotype observed in mutations of the specific TH transporter MCT8 (monocarboxylate transporter 8) gene. Patients manifest severe neurodevelopmental defect and abnormal thyroid function tests, characterized by low serum levels of T4 and rT3 and high serum levels of T3.

Mct8 deficient (Mct8KO) mice replicate the TH changes observed in humans with MCT8 gene mutations even though they lack the severe neurological defects. The animal model has been important to understand the mechanisms underlying the thyroid phenotype in MCT8 deficiency. Brains of adult Mct8KO mice show low T3 uptake and content, as a consequence of impaired intracellular TH transport. The low TH in brain produces a local hypothyroidism and elevated serum TSH concentrations despite high serum T3 levels. In contrast, due to expression of other TH transporters, T3content in liver is increased, resulting in a state of local hyperthyroidism.

Most information on the pathophysiology of the Mct8 deficiency has been derived from studies on adult and late postnatal mice. There are no reports on thyroid function during perinatal period or at birth. Treatment of the neurocognitive defect in humans would require precise information on the ontogeny of thyroid function allowing for early fetal intervention.

We analyzed the serum TH levels and action in cerebral cortex and in liver during the perinatal period of Mct8KO mice to assess how the thyroid abnormalities of Mct8 deficiency develop and to study the thyroidal status of specific tissues.

During the perinatal life the thyroid phenotype of Mct8KO mice is different than that of adult mice. They manifest hyperthyroxinemia at embryologic day 18 and postnatal day 0. This perinatal hyperthyroxinemia is accompanied by manifestations of TH excess as evidenced by a relative increase in the expression of genes positively regulated by T3 in both cerebral cortex and liver. An increased tissue accumulation of T3 and expression of TH alternative transporters, including Lat1, Lat2, Oatp1c1 and Oatp3a1 in cortex and Lat2 and Oatp1b2in liver, suggested that Mct8 deficiency either directly interferes with tissue efflux of TH or indirectly activates other transporters to increase TH uptake.

This study shows an ontogenesis of TH abnormalities in Mct8 deficient mice producing TH excess in the perinatal period.

Nothing to Disclose: AMF, XHL, PG, JB, REW, AMD, SR

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH; SMILE foundation; Sherman family