Biochemical Effects of Thyroid Deficiency on the Developing Brain

Abstract

Abstract— The effects of neonatal thyroidectomy on some constituents of the cerebrum, cerebellum and liver of the rat have been studied during the first 7 weeks of life. In the normal rat between the 6th and 14th post‐natal days the RNA content per unit of DNA in the brain increased by 70 per cent. Although the brain continued to grow from the 14th to the 35th day, the amount of RNA relative to DNA decreased by about 20 per cent. The ratio of protein to DNA increased during the whole period studied and in the cerebral cortex it was more than trebled between the age of 6 and 35 days. The growth of the cerebellum extended over a longer period than that of the cerebrum, its weight increasing by 88 per cent between the ages of 14 and 35 days as compared with a cerebral increase of 34 per cent. The DNA content showed a 50 per cent increase during this period. Qualitatively these maturational changes were not affected by neonatal thyroidectomy. Quantitative changes, which applied equally to the cerebral cortex and brain as a whole, were observed. At the age of 35 days, the weights of the cerebral hemispheres and cerebellum were reduced by thyroidectomy by 20 per cent; the overall DNA content per organ did not change, but the amounts of protein and RNA relative to DNA decreased significantly. It is therefore inferred that thyroid deficiency affects the size of the cells in brain and cerebellum rather than their total number. Conversely, the cell population of the liver was only a quarter of that in the control. There was a small but significant decrease in the hepatic protein and RNA content in the hypothyroid animal. The activities of the following enzymes which served as markers for subcellular fractions in homogenates of cerebral cortex were determined: lactate dehydrogenase for the supernatant, glutamate dehydrogenase for the mitochondrial and glutamate decarboxylase for the synaptosomal fractions. When the activities were expressed on a fresh weight basis a significant decrease by comparison with the control values was observed only in the case of glutamate decarboxylase (—15 per cent at the age of 17–32 days); when the activities were based on DNA content all values were reduced, probably as a result of the general decrease in cell size. Pyrimidine metabolism of brain and liver, studied after the administration of [6‐14C]‐orotic acid, was not affected in either tissue by neonatal thyroidectomy. A small but significant reduction in the incorporation of labelled pyrimidine nucleotides in liver RNA was observed, but no significant decrease in the incorporation in cerebral RNA was found in the hypothyroid rats.

Iodine Deficiency and Brain Development in the Rat

“…While the brain and somatic changes are not as great as have been observed in rats made hypothyroid by other means (Horn 1955;Balazs et al 1968;Oklund and Timiras 1977) there could be other effects, for example those produced by the use of propylthiouracil, 131 I irradiation and diets unsuited for growth and reproduction (Van Middlesworth and Norris 1980) which could account for the difference in degree of response observed between this and other studies. Nevertheless, in our experiment there was a significant retardation in brain development at 21 days both in terms of reduced cell size in the cerebellum and cerebral hemispheres and myelination.…”

Effect of Thyroid on Fatty Acid Biosynthesis in Brain

“…Acetyl-l-«C-CoA and malonyl-l, [3][4][5][6][7][8][9][10][11][12][13][14] C-CoA [20], and the cofactors adenosine triphosphate (ATP), NADH, NADPH, creatine phosphate, and creatine phosphokinase [21] were obtained from commercial sources. Lipids and fatty acid standards were obtained from another laboratory [22], and Cab-O-Sil, PPO, and POPOP were obtained commercially [23].…”

“…Thyroid hormone stimulates amino acid incorporation into brain proteins of immature animals, both in vivo and in vitro, through one or more of the following mechanisms: enhancement of the transfer of soluble, RNA-bound amino acids to microsomal protein [9,11,16,17]; stimulation of RNA synthesis, particularly ribosomal RNA; increase in amino acid incorporation by newly synthesized ribosomes; and readjustment of the permeability barriers [18]. Simultaneously, the hormone influences the activity of a number of enzymes in immature rat brain, including succinic dehydrogenase [10], glutamic acid decarboxylase [3], and galactolipid sulfotransferase [19]. Thyroid hormone also affects the concentration of myelin components.…”

A model of the development of the brain as a construct of the thyroid system.

“…Thyroid hormone availability influences neuronal migration, as evidenced by decreased whole-brain weight and densely packed neurons in the hypothyroid rat cerebellum (63,67). Many genes involved in the process of neuronal migration are sensitive to thyroid hormone (62).…”