title: Placenta passage of the thyroid hormone analog DITPA to male wild-type and Mct8-deficient mice.
abstract: Monocarboxylate transporter 8 (MCT8) deficiency causes severe X-linked intellectual and neuropsychological impairment associated with abnormal thyroid function tests (TFTs) producing thyroid hormone (TH) deprivation in brain and excess in peripheral tissues. The TH analog 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 to determine whether DITPA, when given prenatally, crosses the placenta and affects the serum TFTs and cerebral cortex of embryos. After depletion of the endogenous TH, Mct8-heterozygous pregnant dams carrying both wild-type (Wt) and Mct8-deficient (Mct8KO) male embryos were given DITPA. Effects were compared with those treated with levothyroxine (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 whereas 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 of TH-dependent 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.
authors: Departments of Medicine (A.M.F., X.-H.L., P.G.-I., R.E.W., A.M.D., S.R.) and Pediatrics (R.E.W., S.R.) and the Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Instituto de Investigaciones Biomédicas and Center for Biomedical Research on Rare Diseases (P.G-I., J.B.), Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors: Alfonso Massimiliano
authors: AM
authors: Ferrara
authors: Xiao-Hui
authors: XH
authors: Liao
authors: Pilar
authors: P
authors: Gil-Ibáñez
authors: Juan
authors: J
authors: Bernal
authors: Roy E
authors: RE
authors: Weiss
authors: Alexandra M
authors: AM
authors: Dumitrescu
authors: Samuel
authors: S
authors: Refetoff
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport; D004104:Diiodothyronines / Q000097:blood / Q000493:pharmacokinetics*; D004622:Embryo, Mammalian; D005260:Female; D008297:Male; D008431:Maternal-Fetal Exchange; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011422:Propionates / Q000097:blood / Q000493:pharmacokinetics*; D027981:Symporters; D013963:Thyroid Hormones / Q000493:pharmacokinetics; D013974:Thyroxine / Q000032:analysis / Q000097:blood; D014018:Tissue Distribution
chemical_list: D004104:Diiodothyronines; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D011422:Propionates; C484257:Slc16a2 protein, mouse; D027981:Symporters; D013963:Thyroid Hormones; C082182:3,5-diiodothyropropionic acid; D013974:Thyroxine