The influence of maternal hypothyroxinemia on the expression of the glucose transporters, GLUT1 and GLUT3, in rat fetal brain and placenta was investigated. Fetal growth was retarded in hypothyroxinemic pregnancies, but only before the onset of fetal thyroid hormone synthesis. Placental weights were normal, but placental total protein concentration was reduced at 19 days gestation (dg). Immunoblotting revealed a decreased abundance of GLUT1 in placental microsomes at 16 dg, whereas GLUT3 was increased. Fetal serum glucose levels were reduced at 16 dg. In fetal brain, the concentration of microsomal protein was deficient at 16 dg and the abundance of parenchymal forms of GLUT1 was further depressed, whereas GLUT3 was unaffected. Northern hybridization analysis demonstrated normal GLUT1 mRNA levels in placenta and fetal brain. In conclusion, maternal hypothyroxinemia results in fetal growth retardation and impaired brain development before the onset of fetal thyroid function. Glucose uptake in fetal brain parenchyma may be compromised directly, due to deficient GLUT1 expression in this tissue, and indirectly, as a result of reduced placental GLUT1 expression. Though corrected by the onset of fetal thyroid hormone synthesis, these deficits are present during the critical period of neuroblast proliferation and may contribute to long term changes in brain development and function seen in this model and in the progeny of hypothyroxinemic women.

Maternal thyroid status influences early brain development and, consequently, cognitive and motor function in humans and rats. The biochemical targets of maternal thyroid hormone (TH) action in fetal brain remain poorly defined. A partially thyroidectomized rat dam model was therefore used to investigate the influence of maternal hypothyroxinemia on the specific activities of cholinergic and monoaminergic neurotransmitter metabolic enzymes in the developing brain. Maternal hypothyroxinemia was associated with reduced monoamine oxidase (MAO) activity in fetal whole brain at 16 and 19 days gestation (dg). A similar trend was observed for choline acetyltransferase (ChAT) activity. In contrast, DOPA decarboxylase (DDC) activity was markedly elevated at 21 dg. Further study of these enzymes at 14 dg showed no differences between normal and experimental progeny - suggesting they become TH sensitive after this age. Tyrosine hydroxylase (TyrH) and acetylcholinesterase (AChE) activities were unaffected prenatally. During postnatal development, the activities of TyrH, MAO, DDC and, to a lesser extent, AChE were increased in a brain region- and age-specific manner in experimental progeny. The prenatal disturbances noted in this study may have wide-ranging consequences since they occur when neurotransmitters have putative neurotropic roles in brain development. Furthermore, the chronic disturbances in enzyme activity observed during postnatal life may affect neurotransmission, thereby contributing to the behavioural dysfunction seen in adult progeny of hypothyroxinemic dams.

Maternal thyroid hormone (TH) crosses the placenta and is postulated to regulate fetal brain development. However, TH-dependent stages of fetal brain development remain to be characterised. We have therefore compared the levels of several neuronal and glial cytoskeletal proteins in fetal brains from normal (N) and partially thyroidectomised (TX) rat dams by immunoblotting. Pregnancies were studied both before and after the onset of fetal TH secretion, which occurs at 17.5 days gestation (dg) in the rat. Maternal hypothyroidism disrupted fetal growth, so that fetal body and brain weights were reduced near term. Vimentin expression was unaffected, however, indicating normal acquisition of neuronal and glial precursor cells. Fetal brain levels of glial fibrillary acidic protein (GFAP) were reduced at 21 dg, suggesting delayed astrocytic differentiation, although regression analysis demonstrated appropriate GFAP levels for brain weight. Levels of alpha-internexin, the earliest neurofilament protein expressed in fetal brain were reduced at 16 dg in TX dams, but increased at 21 dg. The ontogeny of neurofilament-L was also perturbed in these pregnancies, with deficient levels apparent at both 16 and 21 dg. These effects on neuronal cytoskeletal proteins were unrelated to fetal brain growth retardation. These findings confirm that maternal hypothyroidism disrupts early fetal brain development. Early disturbances in neuronal differentiation are not corrected by the onset of fetal TH secretion. Such disturbances may contribute to the neurological damage observed in children born to hypothyroxinaemic mothers.

Maternal hypothyroidism during pregnancy impairs brain function in human and rat offspring, but little is known regarding the influence of maternal hyperthyroidism on neurodevelopment. We have previously shown that the expression of neuronal and glial differentiation markers in fetal brain is compromised in hypothyroid rat dam pregnancies and have now therefore extended this investigation to hyperthyroid rat dams. Study groups comprised partially thyroidectomised dams, implanted with osmotic pumps infusing either vehicle (TX dams) or a supraphysiological dose of thyroxine (T4) (HYPER dams), and euthyroid dams infused with vehicle (N dams). Cytoskeletal protein abundance was determined in fetal brain at 21 days of gestation by immunoblot analysis. Relative to N dams, circulating total T4 levels were reduced to around one-third in TX dams but were doubled in HYPER dams. Fetal brain weight was increased in HYPER dams, whereas litter size and fetal body weight were reduced in TX dams. Glial fibrillary acidic protein expression was similar in HYPER and TX dams, being reduced in both cases relative to N dams. alpha-Internexin (INX) abundance was reduced in HYPER dams and increased in TX dams, whereas neurofilament 68 (NF68) exhibited increased abundance in HYPER dams. Furthermore, INX was inversely related to - and NF68 directly related to - maternal serum total T4 levels, independently of fetal brain weight. In conclusion, maternal hyperthyroidism compromises the expression of neuronal cytoskeletal proteins in late fetal brain, suggestive of a pattern of accelerated neuronal differentiation.

Maternal hypothyroidism impairs fetal growth in the rat, but the mechanisms by which this occurs are unknown. Since the fetus derives its glucose supply from the mother, and maternal thyroidectomy may disturb maternal and placental glucose metabolism, we postulated that maternal and/or placental glucose metabolic compromise may contribute to fetal growth retardation in hypothyroid dams. Feto-placental growth, tissue glycogen stores and glucose levels in sera and amniotic fluid were determined in rat dams partially thyroidectomized (TX) before pregnancy and in euthyroid controls. Fetal body weight at 16, 19 and 21 days gestation (d.g.) was related to pre-mating maternal serum total thyroxine (TT(4)) levels; permanent fetal growth retardation occurred in severely (TX(s); pre-mating maternal serum TT(4) 16.19 nM) - but not in moderately (TX(m)) - hypothyroid dams. In TX(s) dams, glycogen concentration was elevated in maternal liver and in the fetal side of the placenta at 16 and 19 d.g., and in the maternal side of the placenta at 19 and 21 d.g., despite maternal euglycemia. In contrast, fetal liver glycogen concentration was deficient in TX(m) dams at 19 d.g. and in TX(s) dams at 19 and 21 d.g., and fetal hypoglycemia occurred in TX(s) dams at 21 d.g. Multiple regression analyses indicate that these fetal deficits are strongly associated with the retardation in fetal growth, while the elevated maternal liver and placental glycogen concentrations have no impact on fetal growth near term. The mechanisms by which severe maternal hypothyroidism permanently retards rat fetal growth remain to be determined.