Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity.
Hypothyroxinemia affects 35-50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers' organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.
Berbel
P
P
Instituto de Neurociencias, Universidad Miguel Hernández and Consejo Superior de Investigaciones Científicas, Sant Joan d'Alacant, Alicante, Spain. pere.berbel@umh.es
Navarro
D
D
Ausó
E
E
Varea
E
E
Rodríguez
A E
AE
Ballesta
J J
JJ
Salinas
M
M
Flores
E
E
Faura
C C
CC
de Escobar
G Morreale
GM
D000818:Animals; D000831:Animals, Newborn; D019521:Body Patterning / Q000502:physiology; D001921:Brain / Q000002:abnormalities* / Q000254:growth & development* / Q000378:metabolism; D002658:Developmental Disabilities / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000254:growth & development*; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D019599:Mossy Fibers, Hippocampal / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013974:Thyroxine / Q000172:deficiency* / Q000378:metabolism / Q000627:therapeutic use
D013974:Thyroxine