MCT8-AHDS Foundation

Placenta passage of the thyroid hormone analogue DITPA to male wild-type and Mct8 deficient mice

Alfonso Massimiliano Ferrara, Xiao-Hui Liao, Pilar Gil-Ibáñez, Juan Bernal, Roy E. Weiss, Alexandra M. Dumitrescu, and Samuel Refetoff
Abstract: 

MCT8deficiency causes severe X-linked intellectualandneuropsychological impairment associated with abnormal thyroid function tests (TFTs) producing thyroid hormone (TH) deprivation in brain and excess in peripheral tissues. The TH analogue diiodothyropropionic acid (DITPA) corrected the TFTs abnormalities and hypermetabolism of MCT8 deficient children but did not improve the neurological phenotype. The latter result was attributed to the late initiation of treatment. Therefore, we gave DITPA to pregnant mice carrying Mct8 deficient embryos, in order to determine whether DITPA, when given prenatally, crosses the placenta, and affects the serum TFTs and cerebral cortex of embryos. After depletion of theendogenousTH, Mct8heterozygous pregnant dams, carrying both wild-type (Wt)andMct8deficient (Mct8KO) male embryosweregiven DITPA. Effectswerecomparedto those treated with L-T4. With DITPA treatment, serum DITPA concentration was not different in the two genotypes, which produced equal effect on serum TSH levels in both groups of pups. In contrast, with L-T4 treatment, TSH did not normalize in Mct8KO pups while it did in the Wt littermates and dams despite higher concentration of serum T4. Finally, both treatments similarly modulated the expression of the TH-dependent genes Shh, Klf9 and Aldh1a3 in brain. Thus, the ability of DITPA to cross the placenta, its thyromimetic action on the expression ofTHdependent genes in brain and its better accessibility to the pituitary than L-T4, as assessed by serum TSH, make DITPA a candidate for the prenatal treatment of MCT8 deficiency.