Long-Term Effects of Late Gestation in Utero Hypoxic Stress on Mood Disorders: Sex and Age Differences

Abstract

Abstract Introduction: In utero insults have been linked with increased fear and anxiety in progeny. In utero hypoxic stress is associated with a multitude of gestational complications such as pregnancy-associated hypertensive disorders and intrauterine growth restriction. Maternal hypertension during pregnancy is also associated with increased mood and anxiety disorders in progeny. However, it is unknown if these associations are due to in utero hypoxic stress. We hypothesized that exposure to late gestational hypoxia will have a long-term impact on anxiety in progeny. Methods: Timed pregnant female Long-Evans rats were exposed to five days (gestational days: 15-20) of chronic intermittent hypoxia (CIH) or room air (normoxia - 21% O2) for 8 hours during their sleep phase. Each CIH cycle was 6 min of 3 min hypoxia (10% O2) and 3 min normoxia (21% O2) for a total of 10 CIH cycles/hour. At weaning (PND 28), progeny was pair-housed with a conspecific of same sex and similar weight. To examine mood and anxiety disorders, we quantified anxiety-related behaviors (time spent in the center of open field arena, marble burying test, social and anti-social behaviors with conspecifics) along with quantifying food intake and circulating sex hormone levels during puberty (postnatal day, PND 40-45) and young adulthood (PND 60-65) in male and female progeny. Results: Gestational CIH did not impact circulating sex hormones or food intake, regardless of sex or age of progeny. However, gestational CIH increased anxiety related behaviors in pubertal females. These effects of gestational CIH on anxiety in pubertal females were not maintained, as these behaviors resolved in young adulthood. Gestational CIH did not impact male progeny, regardless of age. Conclusion: Exposure to CIH during gestation resulted in increased anxiety related behaviors in pubertal female progeny. In utero hypoxia during late gestation may temporarily increase the risk for mood and anxiety disorders in pubertal females.