Programming of the Hypothalamic-Pituitary-Adrenal Axis by Neonatal Intermittent Hypoxia: Effects on Adult Male ACTH and Corticosterone Responses Are Stress Specific

Abstract

Intermittent hypoxia (IH) is an animal model of apnea-induced hypoxia, a common stressor in the premature neonate. Neonatal stressors may have long-term programming effects in the adult. We hypothesized that neonatal exposure to IH leads to significant changes in basal and stress-induced hypothalamic-pituitary-adrenal (HPA) axis function in the adult male rat. Rat pups were exposed to normoxia (control) or 6 approximately 30-second cycles of IH (5% or 10% inspired O₂) daily on postnatal days 2-6. At approximately 100 days of age, we assessed the diurnal rhythm of plasma corticosterone and stress-induced plasma ACTH and corticosterone responses, as well as mRNA expression of pertinent genes within the HPA axis. Basal diurnal rhythm of plasma corticosterone concentrations in the adult rat were not affected by prior exposure to neonatal IH. Adults exposed to 10% IH as neonates exhibited an augmented peak ACTH response and a prolonged corticosterone response to restraint stress; however, HPA axis responses to insulin-induced hypoglycemia were not augmented in adults exposed to neonatal IH. Pituitary Pomc, Crhr1, Nr3c1, Nr3c2, Avpr1b, and Hif1a mRNA expression was decreased in adults exposed to neonatal 10% IH. Expression of pertinent hypothalamic and adrenal mRNAs was not affected by neonatal IH. We conclude that exposure to neonatal 10% IH programs the adult HPA axis to hyperrespond to acute stimuli in a stressor-specific manner.

Intermittent neonatal hypoxia elicits the upregulation of inflammatory-related genes in adult male rats through long-lasting programming effects

“…We have observed a similar phenomenon with intermittent neonatal hypoxia with respect to the behavior of the HPA axis in adults (Chintamaneni et al. ). In that study, less severe intermittent hypoxia (10% O2) produced a different HPA axis “programming” response than more severe intermittent hypoxia (5% O2).…”

“…; Chintamaneni et al. , ). Therefore, discussion of the long‐term effects of late gestation fetal hypoxia is worthwhile in this context, particularly because studies of the long‐term effects of fetal hypoxia are more numerous and comprehensive than neonatal hypoxia in precocial species.…”

“…To put these hypoxic exposures into context, we have shown previously that 10% IH produces trough transcutaneous O2 levels of about 40–50% and 5% IH produces trough transcutaneous O2 levels of about 25–30% (Chintamaneni et al. ). This is relevant clinically as human premature neonates can achieve these severe levels of hypoxia during periods of apnea (Hiatt et al.…”

“…Blood was collected via tail clip at 0, 15, 30, 60, 90, and 120 min post glucose injection as described previously (Chintamaneni et al. ). Blood samples were centrifuged and plasma frozen for subsequent corticosterone, glucose, and insulin analysis.…”

Acute embryonic anoxia exposure favours the development of a dominant and aggressive phenotype in adult zebrafish

“…Similarly, although chronic exposure to moderate hypoxia throughout development reduced basal cortisol levels in 120 hpf zebrafish larvae, it did not affect basal cortisol levels or the response to a net/handling stress protocol in adults [5]. In rats, while several studies have shown that hypoxia can programme the responsiveness of the HPA axis, whether the adult corticosterone stress response is reduced, enhanced or unaffected by fetal or perinatal hypoxia depends on when during development the hypoxic stressor is applied, its severity and duration [20,21]. To what extent HPI axis programming by hypoxia depends on similar exposure windows in zebrafish awaits further experimentation.…”