Effect of Hypothyroidism on Aspartate Transcarbamylase, Uridine Kinase, and DNA Biosynthesis during Cerebellar Development in the Rat

Abstract

Experimental hypothyroidism in the neonatal rat is known to retard cerebellar DNA biosynthesis with a return to normal of the ultimate cell number. Because of the known shift to a later age in the developmental curve for cerebellar thymidine kinase in hypothyroid rats, we studied the activities of aspartate transcarbamylase (ATC) and uridine kinase (UK) during cerebellar development in rats rendered hypothyroid by daily intragastric administration of propylthiouracil to the mother after 18 days gestation. Body weight and cerebellar wet weight in treated animals were noted to be significantly decreased below control values by day 5. Cerebellar DNA was significantly decreased below control values by day 5 with a maximum deficit of 64.9% of control on day 9, and a decrease in deficit to 80.9% of control on day 21. ATC activity in cerebella of hypothyroid rat pups was significantly below that of controls at age 5 days, and by age 15 and 21 days was significantly elevated above control values (91.4, 116, and 154% of controls respectively), thus suggesting a shift to a later age for activity of this enzyme in the hypothyroid state. UK activity in cerebella of hypothyroid pups was significantly below that of activity in control cerebella at age 5 days, but was not significantly different from controls at any of the later ages. Activity of UK in both treated and control cerebella remained relatively elevated by age 21 days with respect to the maximum activity in controls at age 9 days. The shift to a later age in the developmental spectrum of cerebellar ATC activity, an enzyme representative of the <i>de novo</i> pathway for pyrimidine biosynthesis, suggests that the enzyme is involved in the mechanism whereby cerebellar cell division is suppressed and subsequently prolonged in the hypothyroid state. The lack of an influence of hypothyroidism on cerebellar UK activity after day 5 of development supports previous observations that this enzyme may relate in brain to the synthesis of RNA and to cell functions not specifically related to proliferation. The study reveals the differential effects of neonatal hypothyroidism on enzymes representing two of the pathways involved in pyrimidine and nucleic acid biosynthesis during the thyroid hormone-sensitive period of early mammalian brain development, and emphasizes the necessity for further biochemical studies involving tissue pool sizes of <i>in vivo</i> intermediates and serum concentrations of nucleic acid precursors in order to further delineate the relative contribution of each pathway essential for nucleic acid metabolism during development.