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 this study, we show that the oviducts of female rats who were exposed to chronic hypoxia whilst in utero, have reduced telomere length, decreased mitochondrial DNA biogenesis, and increased oxidative stress Our results show that exposure to chronic gestational hypoxia leads to accelerated ageing of the oviduct in early adulthood, and 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 this study, we examine 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 (q‐rtPCR) 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 the 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 up‐regulation of mitochondrial‐specific antioxidant defense 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.

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