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

Gehrand, Ashley; Kaldunski, Mary L.; Bruder, Eric D.; Song, Jia; Hessner, Martin J.; Raff, Hershel

doi:10.14814/phy2.12646

Cited by 4 publications

(4 citation statements)

References 34 publications

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“…Previously, we performed intraperitoneal glucose tolerance tests in male adult rats previously exposed to neonatal intermittent hypoxia and observed no difference in insulin, glucose, or C‐peptide from normoxic controls (Gehrand et al. ). Therefore, in this study, we used arginine stimulation testing as a more sensitive test to determine subtle differences in insulin dynamics (Ye et al.…”

Section: Discussionmentioning

confidence: 81%

“…; Gehrand et al. ). Even though hypoxia leads to spontaneous hypothermia which is thought to be a protective mechanism against severe brain damage and metabolic stress in the neonate (Frappell et al.…”

Section: Discussionmentioning

confidence: 98%

“…Arginine stimulation was chosen rather than glucose tolerance tests because our previous data suggested that glucose tolerance tests are not suitably subtle (Gehrand et al. ). Additionally, we were interested in measuring a glucagon response to arginine stimulation (Ye et al.…”

Section: Methodsmentioning

confidence: 99%

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Sex differences in adult rat insulin and glucose responses to arginine: programming effects of neonatal separation, hypoxia, and hypothermia

et al. 2016

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Acute neonatal hypoxia, a common stressor, causes a spontaneous decrease in body temperature which may be protective. There is consensus that hypothermia should be prevented during acute hypoxia in the human neonate; however, this may be an additional stress with negative consequences. We hypothesize that maintaining body temperature during hypoxia in the first week of postnatal life alters the subsequent insulin, glucose, and glucagon secretion in adult rats. Rat pups were separated from their dam daily from postnatal days (PD) 2–6 for the following 90 min experimental treatments: (1) normoxic separation (control), (2) hypoxia (8% O2) allowing spontaneous hypothermia, (3) normoxic hypothermia with external cold, and (4) exposure to 8% O2 while maintaining body temperature using external heat. An additional normoxic non‐separated control group was performed to determine if separation per se changed the adult phenotype. Plasma insulin, glucose, and glucagon responses to arginine stimulation were evaluated from PD105 to PD133. Maternal separation (compared to non‐separated neonates) had more pronounced effects on the adult response to arginine compared to the hypoxic, hypothermic, and hypoxic‐isothermic neonatal treatments. Adult males exposed to neonatal maternal separation had augmented insulin and glucose responses to arginine compared to unseparated controls. Additionally, neonatal treatment had a significant effect on body weight gain; adults exposed to neonatal maternal separation were significantly heavier. Female adults had significantly smaller insulin and glucose responses to arginine regardless of neonatal treatment. Neonatal maternal separation during the first week of life significantly altered adult beta‐cell function in a sexually dimorphic manner.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 98%

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Sex differences in adult rat insulin and glucose responses to arginine: programming effects of neonatal separation, hypoxia, and hypothermia

et al. 2016

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“…We have previously shown a significant additional neonatal stress response due to the prevention of hypoxia-induced spontaneous hypothermia in the neonate (9,10,23). Furthermore, we have shown long-term alterations in adult physiology subsequent to exposure to maternal-neonatal separation without and with concomitant hypoxia (13,20,21).…”

Section: Introductionmentioning

confidence: 87%

Insulin sensitivity, leptin, adiponectin, resistin, and testosterone in adult male and female rats after maternal-neonatal separation and environmental stress

Raff

Hoeynck

Jablonski

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

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Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.

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Periodic hypoxia, intermittent pain, and caffeine in male and female neonatal rats: corticosterone, insulin resistance, and hepatic gene expression

Gehrand

Phillips

Raff

2023

American Journal of Physiology-Regulatory, Integrative and Comp

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Preterm infants experience multiple stressors including periodic neonatal hypoxia, maternal/caregiver separation, and acute pain from clinical procedures. Although neonatal hypoxia or interventional pain are associated with sexually dimorphic effects that may last into adulthood, the interaction of these common preterm stressors and with caffeine pretreatment remain unknown. We hypothesize that an interaction of acute neonatal hypoxia, isolation, and pain modeling the experience of the preterm infant will augment the acute stress response, and that caffeine routinely given to preterm infants will alter this response. Male and female rat pups were isolated and exposed to six cycles of periodic hypoxia (10% O2) or normoxia (room air control) and/or intermittent pain by administering needle pricks (or touch control) to the paw on postnatal (PD) days 1-4. An additional set of rat pups was pretreated with caffeine citrate (80 mg/kg IP) and studied on PD1. Plasma corticosterone, fasting glucose, and insulin were measured to calculate HOMA-IR (index of insulin resistance). Glucocorticoid-, insulin-, and caffeine-sensitive gene mRNAs were analyzed in the PD1 liver and hypothalamus to evaluate downstream markers of glucocorticoid action. Acute pain with periodic hypoxia led to a large increase in plasma corticosterone, which was attenuated by pretreatment with caffeine. Pain with periodic hypoxia led to a 10-fold increase in hepatic Per1 mRNA expression in males, which was attenuated with caffeine. The augmentation of corticosterone and HOMA-IR at PD1 after periodic hypoxia with pain suggests early intervention to attenuate the stress response may mitigate the programming effects of neonatal stress.

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

Cited by 4 publications

References 34 publications

Sex differences in adult rat insulin and glucose responses to arginine: programming effects of neonatal separation, hypoxia, and hypothermia

Sex differences in adult rat insulin and glucose responses to arginine: programming effects of neonatal separation, hypoxia, and hypothermia

Insulin sensitivity, leptin, adiponectin, resistin, and testosterone in adult male and female rats after maternal-neonatal separation and environmental stress

Periodic hypoxia, intermittent pain, and caffeine in male and female neonatal rats: corticosterone, insulin resistance, and hepatic gene expression

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