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Lumbroso D, Joseph V. Impaired acclimatization to chronic hypoxia in adult male and female rats following neonatal hypoxia. Am J Physiol Regul Integr Comp Physiol 297: R421-R427, 2009. First published June 3, 2009 doi:10.1152/ajpregu.00068.2009.-We tested the hypothesis that neonatal exposure to hypoxia alters acclimatization to chronic hypoxia later in life. Rat pups were exposed to normobaric hypoxia (12% O2; nHx group) in a sealed chamber, or to normoxia (21% O2; nNx group) from the day before birth to postnatal day 10. The animals were then raised in normal conditions until reaching 12 wk of age. At this age, we assessed ventilatory and hematological acclimatization to chronic hypoxia by exposing male and female nHx and nNx rats for 2 wk to 10% O2. Minute ventilation, metabolic rate, hypoxic ventilatory response, hematocrit, and hemoglobin levels were measured both before and after acclimatization. We also quantified right ventricular hypertrophy as an index of pulmonary hypertension both before and after acclimatization. There was a significant effect of neonatal hypoxia that decreases ventilatory response (relative to metabolic rate, V E/V CO2) to acute hypoxia before acclimatization in males but not in females. nHx rats had an impaired acclimatization to chronic hypoxia characterized by altered respiratory pattern and elevated hematocrit and hemoglobin levels after acclimatization, in both males and females. Right ventricular hypertrophy was present before and after acclimatization in nHx rats, indicating that neonatal hypoxia results in pulmonary hypertension in adults. We conclude that neonatal hypoxia impairs acclimatization to chronic hypoxia in adults and may be a factor contributing to the establishment of chronic mountain sickness in humans living at high altitude.hypoxic ventilatory acclimatization; neonatal hypoxia; chronic mountain sickness

We tested the hypothesis that exposure of high-altitude (HA) rats to a period of postnatal normoxia has long-term consequences on the ventilatory and hematological acclimatization in adults. Male and female HA rats (3,600 m, PO2 Ӎ 100 Torr; La Paz, Bolivia) were exposed to normal room air [HA control (HACont)] or enriched oxygen (32% O2; PO2 Ӎ 160 Torr) from 1 day before to 15 days after birth [HA postnatal normoxia (HApNorm)]. Hematocrit and hemoglobin values were assessed at 2, 12, and 32 wk of age. Cardiac and lung morphology were assessed at 12 wk by measuring right ventricular hypertrophy (pulmonary hypertension index) and lung air space-to-tissue ratio (indicative of alveolarization). Respiratory parameters under baseline conditions and in response to 32% O2 for 10 min (relieving the ambient hypoxic stimulus) were measured by whole body plethysmography at 12 wk. Finally, we performed a survival analysis up to 600 days of age. Compared with HACont, HApNorm rats had reduced hematocrit and hemoglobin levels at all ages (both sexes); reduced right ventricular hypertrophy (both sexes); lower air space-to-tissue ratio in the lungs (males only); reduced CO2 production rate, but higher oxygen uptake (males only); and similar respiratory frequency, tidal volume, and minute ventilation. When breathing 32% O2, HApNorm male rats had a stronger decrease of minute ventilation than HACont. HApNorm rats had a marked tendency toward longer survival throughout the study. We conclude that exposure to ambient hypoxia during postnatal development in HA rats has deleterious consequences on acclimatization to hypoxia as adults. development; lungs; breathing POSTNATAL DEVELOPMENT IN MAMMALS is a key period during which environmental stimuli induce immediate physiological responses, but also modulate development, leading to long-lasting physiological alterations in adulthood. Along with other nutrients, oxygen is crucial for adequate development. It is well documented that postnatal hypoxia blunts growth (16) and induces several alterations of the respiratory system in adults. In rats and mice, postnatal hypoxia results in a lung tissue with fewer but larger alveoli, reduced surface-exchange area, limitations of respiratory gas exchange, and signs of pulmonary hypertension (6,31,50). Similarly, adequate development of the respiratory control system is also dependent on postnatal oxygen level. Exposure to hypoxia during early life delays the postnatal maturation of ventilatory response to hypoxia (17, 21), reduces respiratory chemoreflex in adult rats (3,39), and reduces carotid body responses to hypoxia and hypercapnia (25). Typically, the period during which neonatal hypoxia induces such long-term changes includes the first 2 wk of postnatal development (3,31,39,50). These experimental studies linking postnatal hypoxia with blunted chemoreflex responses help to explain results from human studies, showing that minute ventilation (V E), but also hypoxic ventilatory response are decreased in high-altitude residents compared with se...

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