The cellular responses to hYpoxia are poorly understood. To test the hypothesis that ornithine decarboxylase (ODC; L-ornithine carboxy-lyase; EC 4.1.1.17) activity and polyamine concentrations change in response to acute hypoxia we performed the following studies. Pregnant Sprague-Dawley rats inspired various 02 concentrations (9-21%) for various time periods (0.5-48 h) from days 15 to 21 of gestation. In fetal brains we measured the activity of ODC, ODC mRNA, and polyamines. In response to 4-h acute mild hypoxia, ODC activity in fetal rat brain (cerebrum, cerebellum and hippocampus) increased to 330-450% from control values (P < 0.001), after which it declined to control levels in 6-8 h. The 4-h ODC response varied inversely with inspired 02 concentration and was not mimicked by P2 agonist or blocked by 2-antagonist administration. The ODC response was associated with an increase in fetal brain putrescine concentration to 190% above control at 4-6 h (P < 0.01) and an increase in the polyamines spermidine and spermine to about 115% above control at 6-8 h. We also observed that ODC mRNA increased sigificantly after 2-4 h of hypoxia. ODC activity and polyamine concentrations appear to be useful enzymatic markers for fetal brain hypoxia. The magnitude and time course of the acute hypoxic ODC increase were similar to responses to extracellular signals that result in differentiation or cell growth. Thus, the well-defined and regulated ODC activity response may represent a protective mechanism in brain to hypoxia. The brain is known to be particularly vulnerable to oxygen deprivation. Recently, considerable interest has centered on the role of ischemia (lack of blood flow) on brain neurochemistry (1, 2), but relatively little recent work has focused on the neurochemical effects of hypoxia (relative 02 lack) per se (3, 4). In addition, there are few well-documented biochemical or cellular markers of hypoxic effects in brain or other tissues.In this report we present the hypothesis that ornithine decarboxylase (ODC; L-ornithine carboxy-lyase; EC 4.1.1.17) activity could be an enzymatic marker responsive to hypoxia in fetal rat brain. ODC activity is tightly regulated in growing tissue (5) and is sensitive to extracellular signals (6). ODC is the rate-limiting enzyme in polyamine biosynthesis, is highly inducible, has a short half-life (about 20 min), and is absolutely required for cell growth and proliferation (7-9). Thus, ODC activity is an excellent marker for changes in polyamine metabolism, which plays key roles in DNA, RNA, and protein synthesis. Our rationale was that if mild hypoxia affected any of these processes, then ODC activity and polyamine concentrations could be sensitive markers for these changes. Furthermore, because ODC activity is relatively high in growing fetal tissue (10, 11) we expected to be able to detect altered ODC activity in response to hypoxia.We specifically chose maternal hypoxic exposures (9-16% inspired 02), which might be experienced during fetal development, and not ischemic e...