Correlation of DNA accumulation rate with thymidylate synthetase activity in developing rat cerebellum: effect of hypothyroidism.

Abstract

Experimental hypothyroidism in the neonatal rat is known to result in a delay in cerebellar DNA biosynthesis. Because of the known high correlation between rate of DNA biosynthesis and thymidylate synthetase (TS) activity in neonatal hyperthyroidism in the rat, we studied this correlation under conditions of neonatal hypothyroidism. The equation for the least-squares logistic curve describing cerebellar DNA content in neonatal rats as a function of postnatal age (day of birth is day 0), was differentiated to give an expression for the instantaneous rate of cerebellar DNA accumulation in units of nanograms per hour per milligram wet cerebellum. The rate of accumulation of cerebellar DNA in hypothyroid neonatal rats from litters of propylthiouracil-treated dams was significantly (p < 0.05) decreased below control values at 3, 5, and 9 days of age, and significantly elevated at 15 and 21 days of age; the maximum decrease (78% of control) occurred on day 5, and the maximum elevation (266% of control) occurred on day 21. The developmental pattern of cerebellar TS activity in units of picomoles per hour per milligram wet cerebellum, closely paralleled the pattern for DNA accumulation rate in cerebella of both normal and hypothyroid neonatal rats, with cerebellar TS activity in hypothyroid pups significantly decreased below normal on postnatal days, 5 and 9, and significantly elevated on days 15 and 21. During this early developmental time period, a linear correlation of the rates of cerebellar DNA accumulation with the values of cerebellar TS activity gave correlation coefficients of 0.98 and 0.95 for normal and hypothyroid animals, respectively. These data thus support results from our previous study of thyroxine-induced hyperthyroidism, further suggesting that TS may be critical for maintenance of replicative DNA synthesis in the developing rat cerebellum.