Abstract

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.

Highlights

  • ABBREVIATIONS: Alox12, arachidonate 12-lipoxygenase; Alox15, arachidonate 15-lipoxygenase; Chk1, checkpoint kinase 1; Chk2, checkpoint kinase 2; CuZnsod, copper/zinc superoxide dismutase; DNA-PK, DNA-activated protein kinase; Ecsod, extracellular superoxide dismutase; Gp91phox, NADPH oxidase 1; Gpx1, glutathione peroxidase 1; H&E, hematoxylin and eosin; Hif1a, hypoxia-inducible factor 1a; Hmox1, heme oxygenase 1; Nrf2, nuclear respiratory factor 2; Ogg1, 8-oxoguanine DNA glycosylase; P16ink, cyclin-dependent kinase inhibitor 2A; P21, cyclin-dependent kinase inhibitor 1; P22phox, human neutrophil cytochrome b light chain; P53, tumor protein 53; P67phox, neutrophil cytosolic factor 2; Pot1, protection of telomeres protein 1; Ppia, cyclophilin A; Xo, xanthine oxidase

  • At the protein level there was a significant increase in both P53 (P, 0.001) and P16ink (P, 0.05) in the hypoxia-exposed group compared to the normoxia-exposed group (Fig. 5)

  • Chronic gestational hypoxia may arise from maternal hypoxemia [26], maternal smoking [27], or insufficiency of utero-placental blood flow [28]

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Summary

Introduction

ABBREVIATIONS: Alox, arachidonate 12-lipoxygenase; Alox, arachidonate 15-lipoxygenase; Chk, checkpoint kinase 1; Chk, checkpoint kinase 2; CuZnsod, copper/zinc superoxide dismutase; DNA-PK, DNA-activated protein kinase; Ecsod, extracellular superoxide dismutase; Gp91phox, NADPH oxidase 1; Gpx, glutathione peroxidase 1; H&E, hematoxylin and eosin; Hif1a, hypoxia-inducible factor 1a; Hmox, heme oxygenase 1; Nrf, nuclear respiratory factor 2; Ogg1, 8-oxoguanine DNA glycosylase; P16ink, cyclin-dependent kinase inhibitor 2A; P21, cyclin-dependent kinase inhibitor 1; P22phox, human neutrophil cytochrome b light chain; P53, tumor protein 53; P67phox, neutrophil cytosolic factor 2; Pot, protection of telomeres protein 1; Ppia, cyclophilin A; Xo, xanthine oxidase We investigated whether ovarian reserve in the young adult female is influenced by exposure to chronic hypoxia during gestation and determined underlying mechanisms

Objectives
Methods
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