Prenatal Hypoxia Is Associated with Long-Term Retinal Dysfunction in Rats

Stephane L Bourque,Laura M Reyes,Sandra T Davidge,Sharee Kuny,Yves Sauvé,Steven Barnes

doi:10.1371/journal.pone.0061861

Abstract

BackgroundIntra-uterine growth restriction (IUGR) has been associated with increased predisposition to age-related complications. We tested the hypothesis that rat offspring models of IUGR would exhibit exacerbated, age-related retinal dysfunction.MethodsFemale Sprague-Dawley rats (maintained at 11.5% O2 from gestational day 15 to 21 to induce IUGR) and control offspring (maintained at 21% O2 throughout pregnancy) had retinal function assessed at 2 months (young) and 14 months of age (aged) with electroretinogram (ERG) recordings. Retinal anatomy was assessed by immunofluorescence.ResultsDeficits in rod-driven retina function were observed in aged IUGR offspring, as evidenced by reduced amplitudes of dark-adapted mixed a-wave Vmax (by 49.3%, P<0.01), b-wave Vmax (by 42.1%, P<0.001) and dark-adapted peak oscillatory potentials (by 42.3%, P<0.01). In contrast to the rod-driven defects specific to aged IUGR offspring, light adapted ERG recordings revealed cone defects in young animals, that were stationary until old age. At 2 months, IUGR offspring had amplitude reductions for both b-wave (Vmax by 46%, P<0.01) and peak oscillatory potential (Vmax by 38%, P<0.05). Finally, defects in cone-driven responses were further confirmed by reduced maximal photopic flicker amplitudes at 2 (by 42%, P<0.001) and 14 months (by 34%, P = 0.06) and critical flicker fusion frequencies at 14 months (Control: 42±1 Hz, IUGR: 35±2 Hz, P<0.05). These functional changes were not paralleled by anatomical losses in IUGR offspring retinas.ConclusionsThese data support that the developing retina is sensitive to stressors, and that pathways governing cone- and rod-driven function differ in their susceptibilities. In the case of prenatal hypoxia, cone- and rod-driven dysfunction manifest at young and old ages, respectively. We must, therefore, take into account the specific impact that fetal programming might exert on age-related retinal dystrophies when considering related diagnoses and therapeutic applications.

Highlights

Numerous lines of evidence support that fetal hypoxia is an important etiological factor in a number of pregnancy-related complications such as preeclampsia and intrauterine growth restriction (IUGR)
The findings obtained suggest that prenatal hypoxia does cause retinal defects that present at a young age, as well as defects that manifest in later life. We demonstrate that these deficiencies stem from physiological perturbations in retinal function, as opposed to anatomical loss
Dark-adapted retina function Dark-adapted a- and b-wave amplitudes are shown in Figure 1

Summary

Introduction

Numerous lines of evidence support that fetal hypoxia is an important etiological factor in a number of pregnancy-related complications such as preeclampsia and intrauterine growth restriction (IUGR). Studies in rodents have shown that intrauterine compromise, secondary to chronic placental insufficiency, causes altered retinal structure and function [5,6,7]. In these aforementioned studies, the effects of a suboptimal uterine environment were studied exclusively in young offspring, and long-term effects have not been studied. Intra-uterine growth restriction (IUGR) has been associated with increased predisposition to age-related complications. We tested the hypothesis that rat offspring models of IUGR would exhibit exacerbated, age-related retinal dysfunction

Methods

Results

Conclusion