Sex differences in susceptibility to oxidative injury and sleepiness from intermittent hypoxia.
OBJECTIVE
Adult male mice exposed to long-term intermittent hypoxia (LTIH), modeling sleep apnea oxygenation patterns, develop nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent residual hypersomnolence and oxidative injury in select brain regions, including wake-active regions. Premenopausal females are less susceptible to selective oxidative brain injuries. We sought to determine whether female mice exposed to LTIH would confer resistance to LTIH-induced wake impairments and oxidative injuries.


METHODS
Young adult male and female C57BI/6J mice were studied in a university laboratory.


METHODS
Mice were randomly assigned to either LTIH or sham LTIH for 8 weeks. Total (24-h) wake time and mean sleep latency were measured under 2 conditions: rested and following 6 hours of enforced wakefulness. NADPH oxidase activation, carbonylation, and lipid peroxidation assays were also performed to assess sex differences in oxidative responses to LTIH.


RESULTS
In contrast with the significant LTIH-induced wake impairments observed in male mice, females following LTIH showed normal wake times and sleep latencies. Female mice revealed less baseline carbonylation and less carbonylation following LTIH but showed robust NADPH oxidase activation and lipid peroxidation. In contrast with the female relative resistance to LTIH sleepiness, female mice showed more-pronounced sleepiness and delta response after enforced wakefulness.


CONCLUSIONS
Despite a robust oxidative response to LTIH, age-matched female mice may be protected, at least temporarily, from LTIH wake impairments by lower basal carbonylation. In contrast, females show greater wake impairments after sleep deprivation. We hypothesize sex differences in polysomnographic predictors of sleepiness and residual sleepiness in humans with sleep apnea.
Sanfilippo-Cohn
Benjamin
B
Center for Sleep and Respiratory Neurobiology and Department of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Lai
Saien
S
Zhan
Guanxia
G
Fenik
Polina
P
Pratico
Domenico
D
Mazza
Emilio
E
Veasey
Sigrid C
SC
D000818:Animals; D006970:Disorders of Excessive Somnolence / Q000201:enzymology / Q000453:epidemiology*; D005260:Female; D000860:Hypoxia / Q000201:enzymology / Q000453:epidemiology / Q000503:physiopathology*; D028421:Isoprostanes / Q000502:physiology; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D050050:Protein Carbonylation / Q000502:physiology; D011897:Random Allocation; D012737:Sex Factors; D012892:Sleep Deprivation / Q000201:enzymology / Q000453:epidemiology / Q000503:physiopathology; D020178:Sleep Disorders, Circadian Rhythm / Q000201:enzymology / Q000453:epidemiology; D014851:Wakefulness / Q000502:physiology
D028421:Isoprostanes; C438786:isoprostane F2alpha III; D019255:NADPH Oxidases