Effects of gestational intermittent hypoxia on the autoresuscitation response following anoxia-induced apneas in neonatal mice

Abstract

Introduction: Sudden infant death syndrome (SIDS) is the leading cause of death in infants from one month to one year of age. Smoking is a significant risk factor in SIDS, and smoking probably causes intermittent hypoxia in the fetus. Therefore, we modeled the effects of intermittent hypoxia during gestation in mice to determine if gestational intermittent hypoxia would adversely affect the capacity of neonatal mice to autoresuscitate effectively after exposure to anoxic stimuli. A degraded capacity to autoresuscitate could explain, in part, why infants born to mothers who smoke have an increased risk of dying from of SIDS. The primary objective of this study was to investigate the effects of intermittent gestational hypoxia on the autoresuscitation responses to anoxia-induced apneas in neonatal mice. Our hypothesis was that pups born to intermittently hypoxic dams would struggle more to recover from anoxic apneas — would have impaired cardiorespiratory responses to anoxic stress compared to the control mice born to dams exposed to room air during gestation. Methods: We studied C57Bl/6 dams who previously had one litter to prove their capability to breed and rear pups. Dams were placed in either an hypoxic or room air chamber at approximately embryonic day 5 (E5; fifth day of pregnancy). The fractional inspired oxygen concentration (FIO2) was reduced to 11% for 10 minutes, three times per hour, with 10 minute periods of 21% oxygen between them. Each hour of intermittent hypoxia was followed by an hour breathing 21% FiO2. The room air control chamber was maintained at a constant FIO2 of 21% with inflows of compressed air that mimicked the noise and flow of nitrogen in the hypoxic chamber. The dams spent the entirety of their pregnancies in the environmental chambers. Once the pups were delivered, the cages were placed in room air, housing environments. The pups were allowed to stay with their mothers until approximately post-natal day 8 (P8). On P8, each pup was fitted into a head out plethysmograph to measure respiratory flow using a pneumotachograph. We recorded respiratory activity, ECG activity, and body movements (using a piezo sensitive film). The pups were maintained at ~34 degrees C in the pneumotachographic chamber. We measured the highest respiratory rate, highest heart rate, longest apnea, gasp latency, mean heart rate recovery, and mean respiratory rate recovery. Results: The mean heart rate recovery and mean longest apnea (in seconds) doubled in the mice exposed to gestational intermittent hypoxia compared to pups born to dams exposed to room air during gestation. The mean heart rate recovery and mean longest apnea in gestationally hypoxic pups was 41.0 +/- 13.7 seconds and 22.05 +/- 12.0 seconds, respectively. The mean heart rate recovery and mean longest apnea in normal, room air-exposed pups was 22.4 +/- 11.1 seconds and 10.3 +/- 7.0 seconds, respectively. The longest apnea in gestational intermittent hypoxic pups was significantly longer than in control pups (53.0 +/- 13.7 seconds and 19.1 +/- 15.0 seconds). Pups exposed to gestational intermittent hypoxia also had increased mean respiratory rate recovery times and gasp latency times (start of apnea until the first gasp). The average body weight of hypoxic pups was 4.3 grams while the average body weight for the normal pups was 4.9 grams. Conclusion: Gestational intermittent hypoxia was associated with delayed and prolonged the autoresuscitation responses in neonatal mice following acute anoxic exposure. We hypothesize that this is due to changes in the brain’s serotonin system. We are investigating how intrauterine hypoxia may decrease serotonin and serotonergic signaling pathways as changes in serotonergic function may degrade the capacity of mice to autoresuscitate following anoxic gas exposure. NIH/NICHD. HD100823 and NIH/NICHD. HD 107060. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.