Chronic gestational hypoxia accelerates ovarian aging and lowers ovarian reserve in next-generation adult rats.

Chronic fetal hypoxia is a common complication observed in human pregnancy, impacting pregnancies across global contexts. Exposure to chronic intrauterine hypoxia has major short- and long-term consequences for offspring health. However, the impact of chronic gestational hypoxia on female reproductive system development is unknown. We aimed to understand the impact of exposure to chronic fetal hypoxia on the developing female reproductive system. Wistar rat dams underwent normoxia (21%) or hypoxia (13%) during pregnancy. Postnatally, all female offspring were maintained in normoxic conditions into early adulthood. Female rats exposed to chronic gestational hypoxia (13%) during their intrauterine development had decreased ovarian primordial follicular reserve compared to controls (P < 0.05). Adult females who had been exposed to chronic fetal hypoxia had significantly reduced somatic ovarian telomere length (P < 0.05) and reduced ovarian protein expression of KU70, a critical component of the DNA-activated protein kinase repair complex (P < 0.01). Gene expression of NADPH oxidase 2-mediated oxidative stress markers was increased (P < 0.05). Exposure to chronic hypoxia during fetal development leads to accelerated aging of the somatic ovary and decreased ovarian reserve in adulthood. Ovarian aging is highly sensitive to gestational hypoxia, with implications for future fertility in next-generation offspring of high-risk pregnancies.-Aiken, C. E., Tarry-Adkins, J. L., Spiroski, A.-M., Nuzzo, A. M., Ashmore, T. J., Rolfo, A., Sutherland, M. J., Camm, E. J., Giussani, D. A., Ozanne, S. E. Chronic gestational hypoxia accelerates ovarian aging and lowers ovarian reserve in next-generation adult rats.

Chronic fetal hypoxia disrupts the peri-conceptual environment in next-generation adult female rats.

KEY POINTS: Exposure to chronic hypoxia during gestation influences long-term health and development, including reproductive capacity, across generations. If the peri-conceptual environment in the developing oviduct is affected by gestational hypoxia, then this could have implications for later fertility and the health of future generations. In the present study, we show that the oviducts of female rats exposed to chronic hypoxia in utero have reduced telomere length, decreased mitochondrial DNA biogenesis and increased oxidative stress The results of the present study show that exposure to chronic gestational hypoxia leads to accelerated ageing of the oviduct in early adulthood and they help us understand how exposure to hypoxia during development could influence reproductive health across generations. ABSTRACT: Exposure to chronic hypoxia during fetal development has important effects on immediate and long-term outcomes in offspring. Adverse impacts in adult offspring include impairment of cardiovascular function, metabolic derangement and accelerated ovarian ageing. However, it is not known whether other aspects of the female reproductive system may be similarly affected. In the present study, we examined the impact of chronic gestational hypoxia on the developing oviduct. Wistar rat dams were randomized to either normoxia (21%) or hypoxia (13%) from day 6 post-mating until delivery. Post-delivery female offspring were maintained in normoxia until 4 months of age. Oviductal gene expression was assayed at the RNA (quantitative RT-PCR) and protein (western blotting) levels. Oviductal telomere length was assayed using Southern blotting. Oviductal telomere length was reduced in the gestational hypoxia-exposed animals compared to normoxic controls (P < 0.01). This was associated with a specific post-transcriptional reduction in the KU70 subunit of DNA-pk in the gestational hypoxia-exposed group (P < 0.05). Gestational hypoxia-exposed oviducts also showed evidence of decreased mitochondrial DNA biogenesis, reduced mtDNA copy number (P < 0.05) and reduced gene expression of Tfam (P < 0.05) and Pgc1α (P < 0.05). In the hypoxia-exposed oviducts, there was upregulation of mitochondrial-specific anti-oxidant defence enzymes (MnSOD; P < 0.01). Exposure to chronic gestational hypoxia leads to accelerated ageing of the oviduct in adulthood. The oviduct plays a central role in early development as the site of gamete transport, syngamy, and early development; hence, accelerated ageing of the oviductal environment could have important implications for fertility and the health of future generations.