Hadjzadeh, Mousa Al Reza; (1992) Effects of maternal hypothyroxinemia on the expression of biochemical functions in the CNS of the adult rat. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The importance of thyroid hormones in the development and maintenance of normal CNS functions, has long been well established. Iodine-deficient areas are scattered all over the world. Maternal hypothyroxinemia in early pregnancy, as a consequence of iodine deficiency, is associated with an increased incidence of neurological cretinism in the offspring. This condition is irreversible and is manifested in severe cases by mental retardation, deaf-mutism, diplegia of the inferior extremities, gait disorders and sometimes strabismus and stunted growth. In the adult, these conditions cannot be corrected by a normal thyroid state or replacement therapy, suggesting the existence of specific phases in early brain development during which correct exposure to thyroid hormones is of critical importance, and there is a possible fetal dependance on maternal thyroxine. However, the putative biochemical disorders associated with latter have not been studied in detail. The aim of the study was thus to evaluate the biochemical changes in different brain regions due to maternal hypothyroxinemia in an animal model. Seven month old (adult) progeny born to normal and partially thyroidectomised rat dams were used. Total protein, protein profiles of cytosolic and particulate fractions, neuronal cell marker enzymes, myelin metabolic enzymes (oligodendroglial cell markers), and certain lipids were studied. Body weight, brain weight and protein concentrations of brain regions in experimental progeny were apparently unchanged. On the other hand protein profiles of both cytosolic and particulate fractions demonstrated significant alterations in some brain regions. Cytosolic protein bands of 25 kD and 38 kD were significantly changed in medulla, while a 31 kD protein band was absent in this brain region. A 97 kD and a 89 kD cytosolic protein bands were also changed respectively in cerebral cortex and paleocortex of TX dam progeny. A 79 kD protein band was the only particulate protein which significantly increased in medulla in the experimental progeny. Significant changes were observed in myelin metabolic enzymes in specific brain regions of experimental progeny, e.g. CNPase activity was decreased in medulla by 37% (p<0.05) and in midbrain by 32% (p<0.05), and 5'-nucleotidase activity was decreased significantly in the same regions by 33% (p<0.05) and 35% (p<0.05), respectively. In paleocortex, oleate esterase activity (a myelin metabolic enzyme) was significantly increased by 39% (p<0.05), whereas β-D glucuronidase activity (a neuronal marker) was significantly decreased by 30% (p<0.05), N-acetyl-β-D galactosaminidase activity (a general glial marker) was unchanged and the activity of sphingomyelinase was also unchanged in all brain regions studied. No change was observed in the concentration of cholesterol (a major component of the myelin lipid) in any brain region but other two specific myelin lipids, cerebroside and sulphatide demonstrated significant changes in experimental progeny. The former was decreased in medulla and the latter also decreased in the midbrain and paleocortex of progeny. Changes in myelin metabolic enzymes and lipids have suggested a deficit in myelin metabolism of adult progeny from partially thyroidectomised dam. In conclusion, these findings indicate that the effects of maternal hypothyroxinemia are brain region-specific. These effects are also irreversible, since they are observed in adult progeny and persist despite a normal thyroid state. It is well known that glial cell proliferation and acquisition in the rat occurs postnatally, when the thyroid is functionally active. It is argued that the thyroid hormone environment of the fetus, before the onset of an independent fetal hypothalamic-pituitary-thyroid axis may be of critical importance for the expression of glial functions after birth. It is suggested that maternal hypothyroxinemia in early pregnancy may cause irreversible brain region- specific biochemical changes in adult progeny and thyroid hormones in early pregnancy may have an epigenic effect on the function of the adult CNS.

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