Al-Yatama, Fatima Ibrahim Khalaf; (1995) Maternal hypothyroxinemia and fetal brain development: A biochemical, enzymic, metabolic and molecular biological investigation. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The developing brain is the most susceptible tissue to changes in the level of thyroid hormone (TH). Abnormal intrauterine TH environment may lead to catastrophic disturbances in brain development which are irreversible if thyroid status is not corrected. Inappropriate transference of maternal TH to the fetus was recently reported to affect many biochemical, neurotransmitter, and metabolic parameters in adult, juvenile, and fetal brains. Therefore, the effects of intrauterine TH environment on the expression of biochemical, enzymatic, metabolic, and molecular biological functions of the developing brain was investigated using fetuses from partially thyroidectomised (TX) rat model at different stages of gestation. Maternal hypothyroxinemia adversely affected the fetal brain growth as manifested by a significant decrease in the DNA content, wet weight, and proteiniDNA ratio at 15, 19, and 22 days of gestation (dg) respectively. The RNA concentration and RNA:DNA ratio were also found to be reduced at 19 dg. The protein phosphate and inorganic phosphate were both reduced in fetal brain from TX dams at 15 dg, then substantially increased at 19 dg. A further increase at 22 dg was also observed for the inorganic phosphate. The lipid phosphate concentration was increased in fetal brain from TX dams at 19 and 22 dg. In addition, maternal hypothyroxinemia was found to affect most of the aforementioned biochemical parameters in the fetal liver. With respect to the placenta, maternal hypothyroxinemia was found to reduce the RNA:DNA ratio and placental weight at 19 and 22 dg respectively, and significantly increase the RNA concentration at 22 dg. the protein phosphate concentration was found to be affected too. This was manifested by the significant decrease at 15 dg, followed by a substantial increase at 19 dg. Maternal hypothyroxinemia was without effect on the placental or fetal brain total lipid concentrations, while the cholesterol concentration was significantly reduced in fetal brain at 15 dg followed by an increase at 22 dg. Similar increase was also observed in the placenta and fetal liver. In the fetal liver a significant increase in the total lipid concentration was observed at 22 dg. Maternal hypothyroxinemia significantly increased the protein kinase C (PKC) activity in the fetal brain at 15 dg, which was then reduced at 19 dg. The cAMP-dependent protein kinase (PKA) activity, on the hand, was within normal values at all gestational ages studied. The effect of maternal hypothyroxinemia on Na+ K+-ATPase and Ca2+ Mg2+-ATPase was studied too. The activity of both enzymes were significantly reduced at 15 dg and 19 dg. This reduction was sustained at 22 dg for the Na+K+-ATPase activity, whereas for Ca2+ Mg2+-ATPase activity a significant increase was observed. Measurement of the activity of the dephosphorylating enzymes; acid phosphatase and alkaline phosphatase, revealed no obvious effect of maternal hypothyroxinemia upon their activity. The glucose uptake and metabolites of glucose utilisation: CO2, amino acids, protein, lipid, and protein lipids were all found to be affected at all gestational ages studied, except for CO2 where no changes were observed at 21 dg in the experimental fetal brain. Finally the mRNA expression of the glucose transporter (GLUT 1) was found to be significantly reduced in the fetal brain from TX dams at 16 dg, whereas no changes were observed at 19 and 21 dg. It can be concluded, therefore, that maternal hypothyroxinemia causes a range of damaging effects on the fetal brain development which may be irreversible and, as no significant effects of maternal hypothyroxinemia were observed on the placental development, it is suggested that the placenta in the hypothyroxinemic condition is likely to function normally and the observed changes in the fetal brain development are related directly to maternal TH status.

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