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

Background: 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: Female Sprague-Dawley rats (maintained at 11.5% O-2 from gestational day 15 to 21 to induce IUGR) and control offspring (maintained at 21% O-2 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. Results: Deficits in rod-driven retina function were observed in aged IUGR offspring, as evidenced by reduced amplitudes of dark-adapted mixed a-wave V-max (by 49.3%, P<0.01), b-wave V-max (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 (V-max by 46%, P<0.01) and peak oscillatory potential (V-max 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. Conclusions: These 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.