Changes in Hepatic Iodothyronine Metabolism during Ontogeny of the Chick Embryo*

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Abstract
As a model of the changes in peripheral iodothyronine metabolism that occur during ontogeny, we have studied the metabolism of l25I-labeled T4 and several of its partially deiodinated derivatives by the liver of the chick embryo. Homogenates of livers obtained from chicks varying in embryonic age from 8 days to the time of hatching (20–21 days) were incubated with various iodothyronines, all labeled with 125I in their outer or phenolic ring. Rates and products of the reactions were analyzed by paper chromatography of whole homogenates. In livers from embryos of all ages studied, the addition of dithiothreitol (DTT; 2 mM) enhanced the rate of metabolism of the iodothyronines T4, T3, and rT3. Marked age-related changes in the metabolism of the iodothyronines were apparent; these were evident in the absence of DTT, but were most clearly seen in specimens to which DTT had been added. rT3 was degraded very rapidly, even in livers from 8-day-old embryos, but its rate of degradation increased progressively with increasing age of the embryo up to the time of hatching. Outer ring (5′-) monodeiodination, giving rise to 3,3′-diiodothyronine (3,3′-T2), was the predominant, and perhaps the sole, pathway of rT3 metabolism throughout this period of embryogenesis. Age-related changes in the metabolism of T4 and T3 were similar to one another, but differed greatly from those seen in the case of rT3. In specimens enriched with DTT, the rates of metabolism of T4 and T3 were moderately rapid in livers from 12-day-old embryos and then increased abruptly, remaining very rapid in livers from embryos through 18 days of age. Rapid degradation of T4 was not due to 5′-monodeiodination, since very little T3 was generated from T4. In addition, since results obtained were similar during incubations under air and N2, oxidative degradation of T4 was apparently not important. Rather, during this period, inner ring (5-) monodeiodination appeared to be by far the predominant pathway of metabolism of both T4 and T3) leading to the formation of rT3 from T4 and 3,3′-T2 from T3. In livers from 19- and 20- day-old embryos, the latter obtained just before hatching, the overall metabolism of both T4 and T3 slowed abruptly and progressively owing to a decrease in the rate of 5-monodeiodination. Concomitantly, 5′-monodeiodination of T3 and T4 became more prominent, leading to increased generation of T3 from T4. These maturational changes in T4 and T3 metabolism coincided in time with penetration of the air sac by the embryo's beak and initiation of air breathing, a process termed internal pipping. Premature maturational changes in T4 and T3 metabolis m, very similar to those that occurred spontaneously in 19- and especially 20-day-old embryos, were induced within 2 days by the single injection of 200 μg hydrocortisone onto the allantoic membrane of immature embryos. It is concluded that hepatic iodothyronine metabolism in the immature embryo is directed so as to prevent the accumulation of T3 derived from T4. This is achieved by the rapid transformation of T4 to rT3, rather than T3, and by the rapid degradation of both rT3 and any T3 that is formed. Maturation of iodothyronine metabolism occurs during the last 2 days in ovo and is directed toward sparing T4) making it a more efficient source of T3, and preserving the T3 formed. These characteristics of hepatic T4 and T3 metabolism reflect marked activity of 5-monodeiodinating mechanisms for these hormones in the immature embryo, with a decrease in 5-monodeiodinations and an increase in 5′-monodeiodinations during maturation. The role that these changes in iodothyronine metabolism play in fetal ontogeny remains uncertain.