ESTROGEN REGULATION OF PLACENTAL P-450 CHOLESTEROL SIDE-CHAIN CLEAVAGE ENZYME MESSENGER-RIBONUCLEIC-ACID LEVELS AND ACTIVITY DURING BABOON PREGNANCY

The present study was conducted to determine whether estrogen regulate s the P-450 cholesterol side-chain cleavage (P-450scc) enzyme componen t of the progesterone biosynthetic pathway in the placenta during the second half of baboon pregnancy. Placental estrogen formation was supp ressed by removing the fetus, i.e. fetectomy, and thus fetal adrenal C -19-steroid estrogen precursors, on day 100 of baboon gestation (term - 184 days. P-450scc activity and messenger ribonucleic acid (mRNA) le vels were then determined in placentas obtained on day 160 after fetec tomy alone and after fetectomy and sc administration of the estrogen p recursor androstenedione or estradiol benzoate. Placentas were maintai ned in situ after fetectomy, and placental villi were comprised of syn cytiotrophoblasts that seemed morphologically normal, based on their h istology and immunocytochemical expression of pregnancy-specific-beta( 1)-glycoprotein. In untreated baboons, peripheral serum estradiol incr eased with advancing gestation, and mean (+/-SE) concentrations were 1 .22 +/- 0.05 ng/ml on days 101-160 of gestation. After fetectomy serum estradiol concentrations decreased to 24% (P < 0.01) of normal. Andro stenedione or estradiol administration after fetectomy increased serum estradiol levels to values that were 57% (P < 0.01) of, or 90% (P < 0 .001) greater than intact controls, respectively. Placental P-450scc s pecific activity, determined on a mitochondrial-enriched fraction of v illous tissue, was 281.1 +/- 15.0 pmol pregnenolone plus progesterone formed per mg mitochondrial protein in untreated control baboons. Fete ctomy resulted in a 52% decrease (P < 0.001) in placental P-450scc act ivity. Administration of androstenedione or estradiol after fetectomy increased P-450scc activity to values that were not significantly diff erent from control. P-450scc mRNA levels were quantified by competitiv e RT-PCR. P-450scc mRNA levels in placental villous tissue of fetectom ized baboons was 38% lower (P < 0.01) than that in the intact controls (110.0 +/- 5.9 attomoles/mu g RNA). The administration of androstened ione after fetectomy restored P-450scc mRNA to a level that was not di fferent from the untreated controls. The results of this study show th at there was close association between the levels of estrogen and the specific activity of and the mRNA levels for placental P-450scc in the second half of baboon pregnancy. Therefore, we propose that the P-450 scc enzyme that catalyzes the conversion of substrate cholesterol to p regnenolone is regulated, for the most part, by estrogen in the primat e placenta.