Whereas the greatest relative increase in body mass occurs during the third trimester of fetal life, the source of the cholesterol that supports this growth is uncertain. These studies used I3Hlwater and "2'I-cellobiose-labeled low density lipoproteins to quantitate absolute rates of cholesterol acquisition in vivo by the fetus of the rat. Preliminary studies demonstrated that 13Hlwater administered intravenously to the mother rapidly equilibrated with the body pool of water in the fetus and that 22-,ug atoms of H from the water pool were incorporated into each micromole of newly synthesized cholesterol. After administration of 13Hlwater to pregnant rats, the rates of sterol synthesis per 100 g of whole body weight were severalfold higher in the fetus than in the dams. Individual organs of the dam such as the liver, however, had much higher synthetic rates than those in the fetus. When maternal hepatic cholesterol synthesis was suppressed by cholesterol feeding, newly synthesized cholesterol disappeared from the maternal blood yet there was essentially no change in the rate of appearance of newly synthesized sterol in the fetus, placenta, and fetal membranes. The placenta did take up low density lipoproteins at rates equal to about one-third of that seen in the maternal liver, but none of the apolipoprotein or cholesterol was transferred to the fetus. These studies indicate that the rat fetus receives little or no cholesterol from the mother but, rather, satisfies its need for cholesterol during fetal development through local synthesis. Furthermore, the fetal membranes appear to be an important site for sterol synthesis in the fetal compartment.
We have shown that serum bile acid concentrations are elevated in human infants reflecting physiologic immaturity of the enterohepatic circulation. To define further the ontogeny of bile acid metabolism in mammals, we examined maturational changes in the serum concentration of total cholate conjugates by radioimmunoassay in fetal, neonatal, suckling, and mature Sprague-Dawley rats. Fetal (21st day) levels were low (1.4 +/- 0.23 microM; X +/- S.E.), possibly due to minimal enterohepatic cycling in utero. The concentrations in samples obtained minutes after birth, prior to suckling were significantly elevated (12.6 +/- 2.37; p less than 0.001 vs. fetal); these high values persisted after feeding was initiated (6 hr = 13.5 +/- 0.99), but fell at 12 hr (5.2 +/- 0.81) and remained unchanged for the duration of the first day. Serum values fluctuated briefly, being 9.6 +/- 0.73 on Day 4, and the rose progressively through the suckling period (Day 10 = 7.2 +/- 9.57; Day 14 = 10.4 +/- 1.70; Day 21 = 16.8 +/- 1.93); there was a dramatic peak after weaning (Day 28 = 21.8 +/- 1.53). The serum concentration of cholate conjugates then fell (5.6 +/- 0.68 on Day 42) to achieve adult levels by 56 days (4.0 +/- 0.55), a value substantially different from that of all developing animals (p less than 0.025). These data corroborate studies which suggest that a period of physiologic cholestasis occurs in the developing rat. Serum cholate conjugate concentrations likely reflect interrelated morphologic alterations (bile canalicular structure and portal blood flow) and physiologic changes (bile acid synthesis, pool size, and transport) occurring in the enterohepatic circulation during early life.
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