Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology

Supervisor

Dr. John Ciriello

Abstract

Obstructive sleep apnea (OSA) is a chronic disorder involving repetitive interruptions in breathing during sleep. Sufferers of OSA are exposed to chronic intermittent hypoxia (CIH), characterized by cyclical reductions in oxygen availability. A number of studies have established a link between OSA and various cardiovascular and metabolic comorbidities in adulthood, including hypertension, obesity, and type II diabetes. While the consequences of OSA in adults have been well described, the cross-generational impact of this condition and potential effects on fetal development are not known. Epidemiological and animal studies have demonstrated that physiological insults during pregnancy lead to diminished growth of offspring and impairments in long-term metabolic health. The following studies were performed to investigate the alteration of metabolic health as a result of gestational exposure to CIH, the underlying physiological condition in OSA. Exposure to CIH during pregnancy resulted in asymmetrically growth restricted offspring with lower birthweights compared to normoxic offspring. In adulthood, male CIH offspring had higher body weights and higher visceral adipose tissue. Gestational CIH caused impairments in glucose homeostasis, as male CIH offspring were hyperglycemic, hyperinsulinemic, and showed impaired early-stage glucose tolerance in adulthood. Molecular analysis revealed that CIH offspring have diminished regulation of hepatic gluconeogenic pathways by the Liver X Receptor (LXR), leading to increased expression of hepatic markers associated with gluconeogenesis and increased glucocorticoid signalling. Adult male CIH offspring were also hypercholesterolemic with decreased expression of LXR target genes associated with cholesterol metabolism and excretion. Taken together, these results describe changes in hepatic function that result in impaired regulation of glucose and cholesterol homeostasis in adulthood. The findings of this thesis provide insight into the long-term consequences of insult during gestation, and highlight the importance of giving consideration to OSA in assessing maternal health and predicting fetal outcomes.


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