The regulation and role of corticosteroids during fetal development

Fetal mouse txssues were incubated with ¹⁴C-corticosterone together with ³H-11-dehydrocorticosterone and the steroids were extracted and separated chromatographically to determine the ratio reduction/dehydrogenation. Between gestational days 14 and 19, the ratio in placenta increased from 6.3 to 23.4; in brain from 0.06 to 0.63; in gut from 0.1 to 0.5; and in liver from 0.29 to 8.3. In lung, the ratio rose from 0.16 to 6.7 only after day 16, two days later. Treatment of mothers 16 h earlier with 200 μg dexamethasone increased the ratio in lung and placenta on day 16 but not earlier. After injection of ³H-corticosterone into mothers, the amount of ³H-11-dehydrocorticosterone, which was 98% of the total on day 14, declined, while unchanged corticosterone increased at least tenfold in all tissues examined between days 14 and 19. A receptor has been found in fetal brain with K[sub D]= 8.3 nM which binds ³H-dexamethasone to the extent of 0.14 pmoles/mg protein on day 14. The number of receptor sites did not increase with gestational age, indicating that these are not critical in initiating steroid-dependent processes. In fetal brain and placenta, receptors bound both ³H-corticosterone and 11-dehydro-corticosterone. In cytosol and nucleus, both labelled steroids were displaced competitively by each other. The ³H-ll-dehydro-corticosterone-receptor complex not only entered the nucleus but was bound to chromatin slightly more than was the hormone corticosterone. Of parameters reflecting changing levels of active hormone in fetal tissues, the in vitro incorporation of ¹⁴C-leucine, ³H-uridine and ³H-thymidine into acid-insoluble components of tissues were the most sensitive. The incorporation of these precursors decreased between days 14 and 19 by as much as 90%. The deposition of glycogen varied in different fetal tissues but did not reflect hormonal changes. By all parameters, the injection of mothers with 200 μg dexamethasone 16 h earlier resulted in acceleration of the normal pattern, producing values on day 14 which were normally observed on days 15-19. Fetuses which had been treated with dexamethasone in utero were born and appeared normal. Other steroid-induced processes included increased amino acid content of fetal brain and the conversion of glucose to fructose in fetal liver and gut. It is concluded that the regulation of corticosteroids is accomplished not simply by activation of the fetal pituitary-adrenal axis, but by the interconversion in individual tissues of corticosterone and its 11-dehydro metabolite. The 11-dehydrocorticosterone is not only an abundant metabolite, but serves as a reservoir of potential hormone and can compete with corticosterone for both cytosol and nuclear receptor sites. Since it binds to chromatin, it is possible that 11-dehydrocorticosterone exerts actions at the transcriptional level. Corticosteroids exert their effects on fetal development at an earlier stage than has been hitherto reported.Medicine, Faculty ofBiochemistry and Molecular Biology, Department ofGraduat