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The chemoreflex pathway undergoes postnatal maturation, and the perinatal environment plays a critical role in shaping respiratory control system. We investigated the role of prenatal hypoxia on the maturation of the chemoreflex neural circuits regulating ventilation in rat. Effects of hypoxia (10% O2) from the 5th to the 20th day of gestation were studied on male offspring at birth and on postnatal days 3, 7, 21 and 68. Maturation of the respiratory control system was assessed by in vivo tyrosine hydroxylase (TH) activity measurement in peripheral chemoreceptors (carotid bodies, petrosal ganglia), and in brainstem catecholaminergic cell groups (A2C2c and A1C1 areas in the medulla, A5 and A6 areas in the pons). Resting ventilation and ventilatory response to hypoxia were evaluated as functional sequelae. In peripheral structures, prenatal hypoxia reduced TH activity within the first postnatal week and enhanced it later. In contrast, in central areas, prenatal hypoxia upregulated TH activity within the first postnatal week and downregulated it later. The in vivo TH activity impairment is therefore tissue specific, with an opposite effect on the peripheral and central neural circuits. A shift of the effect of prenatal hypoxia occurred between 1 and 3 weeks, indicating a postnatal temporal effect of prenatal hypoxia. An important period in the development of the chemoafferent pathway occurred between the first and the third postnatal week. Functionally, prenatal hypoxia impaired resting ventilation and ventilatory response to hypoxia. The alterations of the catecholaminergic components of the chemoafferent pathway resulting from prenatal hypoxia might contribute to impair postnatal respiratory behaviour.

Before birth, the peripheral chemoreceptors located in the carotid bodies (CB) are adapted to the low fetal Po(2) and are relatively insensitive to hypoxia. After birth, the sensitivity of the CB to hypoxia is reset in response to the rise in Po(2). The mechanism underlying this resetting, which requires several days to complete, remains unknown. We have investigated the possibility that the hypoxia-inducible factors HIF-1alpha and HIF-2alpha, which are activated by oxygen deprivation, are involved in this resetting process. Accordingly, we used immunostaining and densitometry to quantitate the levels of the HIF-1alpha and HIF-2alpha proteins in the rat CB during early perinatal life and after exposure to in vivo hypoxia during adolescence. Tyrosine hydroxylase (TH) was used as a marker for catecholaminergic neurons and oxygen-sensitive cells in the CB. Double-immunostaining revealed constitutive expression of HIF-1alpha in both glomus cells (TH+) and sustentacular cells (TH-) of the CB of adolescent rats. However, immunoreactivity toward HIF-2alpha was restricted to glomus cells. After exposure to hypoxia (8% O(2), 6 h), the expression of HIF-1alpha was selectively up-regulated in glomus cells and apparent translocation of both HIF-1alpha and HIF-2alpha to the nucleus was observed. Both of these proteins were expressed constitutively in the CB during the perinatal transition period. During the first postnatal week, the intensity of immunostaining for HIF-1alpha in glomus cells decreased markedly, whereas the level of HIF-2alpha remained constant. We suggest that this selective down-regulation of HIF-1alpha may be involved in the postnatal maturation of CB responsiveness to hypoxia.

1. To define the effects of prenatal hypoxia on the postnatal development of the chemoafferent pathway, ventilation and metabolism, pregnant rats were exposed to normobaric hypoxia (10 % oxygen) from embryonic day 5 to embryonic day 20. Offspring were studied at 1, 3 and 9 weeks of age in three separate protocols. 2. Prenatal hypoxia decreased the dopamine content in the carotid bodies at all ages, and decreased the utilisation rate of noradrenaline in the caudal part of the A2 (A2c), A1 and A5 noradrenergic brainstem cell groups at 3 weeks after birth. At 9 weeks of age, the level of dopamine in the carotid bodies was still reduced but the utilisation rate of noradrenaline was enhanced in A1. 3. Rats from dams subjected to hypoxia during pregnancy hyperventilated until 3 weeks after birth. In these rats, the biphasic hypoxic ventilatory response was absent at 1 week and the increase in minute ventilation was amplified at 3 weeks. 4. Prenatal hypoxia disturbed the metabolism of offspring until 3 weeks after birth. A weak or absent hypometabolism in response to hypoxia was observed in these rats in contrast to control animals. 5. Prenatal hypoxia impairs the postnatal development of the chemoafferent pathway, as well as the ventilatory and metabolic responses to hypoxia. These alterations were mostly evident until 3 weeks after birth.