DEVELOPMENTAL REGULATION OF PREPROENKEPHALIN (PENK) GENE-EXPRESSION IN THE ADRENAL-GLAND OF THE OVINE FETUS AND NEWBORN LAMB - EFFECTS OF HYPOXEMIA AND EXOGENOUS CORTISOL INFUSION

Development of the fetal adrenal gland is crucial not only for maturat ion of several fetal organ systems and the initiation of parturition, but also for the development of the fetal response to stress. The enke phalin-related peptides are present in the chromaffin cells of the fet al adrenal medulla and are secreted in response to stress and with sym pathetic stimulation. However, changes in expression of preproenkephal in (PENK) with gestation and in response to stress have not been studi ed in detail. Therefore we examined the developmental pattern of PENK gene expression in the adrenal gland of fetal and newborn lambs, and o f adult sheep. We also determined whether levels of PENK mRNA in the f etal adrenal gland changed in response to exogenous glucocorticoids in late gestation, or in response to hypoxemia. Adrenal glands were remo ved from fetal sheep, lambs and adult sheep at different stages of dev elopment for measurement of PENK mRNA. Cortisol was infused (5 mu g/mi n) for 12, 24 or 96 h beginning on day 124-129 of gestation. Moderate hypoxemia was induced for 48 h beginning on day 126-130, or at day 134 -136 of gestation, by lowering the maternal fractional inspired oxygen . At the end of the treatment periods, the ewes and fetuses were eutha nized. Adrenal PENK mRNA were measured by Northern blot analysis. PENK mRNA levels in fetal adrenals were significantly higher (P<0.05) on d ays 140-141 of gestation than earlier in pregnancy, and then decreased significantly with the onset of parturition (days 142-146), After cor tisol infusion to the fetus for 96 h there was a significant reduction in adrenal PENK mRNA levels. Hypoxemia resulted in a significant incr ease in PENK mRNA levels in fetuses at day 126-130 of gestation, but n ot at the later time in pregnancy when endogenous plasma cortisol conc entrations were higher. We conclude that there is a decrease in levels of PENK mRNA in the fetal adrenal gland before parturition at the tim e of the endogenous prepartum rise in plasma cortisol. Hypoxemia led t o an elevation of PENK mRNA levels in fetuses at less than 130 days, b ut after that time, when the basal and stimulated cortisol responses h ad risen, there was no significant effect of hypoxemia on PENK mRNA. C ortisol infusion to the fetus at this stage of pregnancy resulted in a decrease in adrenal PENK mRNA levels. We suggest that cortisol may pl ay an important role in the regulation of fetal adrenal PENK mRNA leve ls and enkephalin synthesis by the adrenal gland of the fetal sheep.