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ExtractIn the lung of the rabbit fetus there was a rise in concentration of total lipids before term, the phospholipids constituting the major fraction. The concentrations of phosphatidylethanolamine and lecithin rose concurrently until day 28 when phosphatidylethanolamine concentration dropped, but lecithin continued to rise to term. From day 28 to term in the nonbreathing fetus there was an increase of 300 % in acetone-precipitated surface-active lecithin found almost entirely in the residual parenchyma after wash with little increase in this fraction in alveolar wash. After breathing for 1 hour there were increases in total alveolar lecithin 3-5 fold over nonbreathing fetal lung while increases in acetoneprecipitated alveolar wash lecithin from nonbreathing to breathing lung were 20-30 fold. Enzymatic reactions were studied in vitro according to the pathways for the de novo synthesis of lecithin and phosphatidylethanolamine as follows:CDP-choline incorporation declined steadily during gestation, although at term still showed rapid incorporation. The methylation reaction (2) showed peak incorporation on day 28 of gestation, at beginning viability. CDP-ethanolamine incorporation was the most active in vitro pathway studied peaking on days 25-26. Serine incorporation showed little activity, following a pattern of incorporation similar to that of CDP-ethanolamine. Activity of all pathways was found in microsomes. Methylation was also found in mitochondria1 fraction of the term fetus and adult and in the cell-free soluble fraction from adult alveolar lavage. Reaction rates were similar from CDP-choline incorporation in both fetal and adult lung homogenate, but fetal lung incorporated methyl groups faster than adult lung. Intermediate compounds of methylation reaction were not found in alveolar wash of fetal lung, but were isolated from adult alveolar wash. Methylation in lung was pH sensitive, peak incorporation was seen at pH 7.8. Addition of ethanol or boiling one minute did not stop methylation. After breathing, those rabbit fetuses delivered by cesarean section after 28 full days of gestation synthesized 100 % of surface-active alveolar lecithin by one hour of breathing, 90 % of incorporation was with 3 H-choline, 10 % with ( 14 CH,)-methionine. Much less incorporation into alveolar wash lecithin was seen with the breathing term fetus, but much more surface-active alveolar wash lecithin was isolated than from the fetus of 28 full days of gestation. SpeculationThe most important pathway in rabbit fetal development and in the newborn rabbit for the de novo synthesis of surface-active alveolar lecithin is the incorporation of CDP-choline. Although there is good correspondence between the concentrations of lecithin and phosphatidylethanolamine in fetal lung and the enzymatic activities studies in vitro, once breathing begins there is little correspondence between in viuo and in vitro biosynthesis of lecithin by fetuses of the same gestational age. In the rabbit fetus and newborn the methylation reaction appears t...