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Jeff Gidday, Krystal C Belmonte, Nicholas A Lanson, Jarrod C. Harman; Preconditioning Across Generations: Intermittent Hypoxia in F0 Mice Promotes Neuroprotection from Retinal Ischemia in F1 Offspring. Invest. Ophthalmol. Vis. Sci. 2018;59(9):763. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
That a preconditioning stress can induce a transient (lasting hours to days), endogenous neuroprotective state against ischemia was shown experimentally decades ago. We and others recently documented that repetitive presentations of stress stimuli induce longer-lasting (weeks to months) changes in phenotype, an epigenetic response which proved efficacious for inducing innate resilience to the more protracted cell loss that characterizes retinal neurodegenerative diseases (glaucoma, diabetes). Given recent transgenerational epigenetics studies wherein disease phenotypes are inherited secondary to adverse stress experienced by one or both parents, the present study was undertaken to determine if stress-induced, beneficial phenotypes could be extended even further - to the next generation.
Adult, male and female Swiss-Webster ND4 mice (F0), housed separately, were briefly exposed to systemic hypoxia 3x/wk for 16 wks; age- and sex-matched controls were not exposed. A week later, F0xF0 mating pairs were established between hypoxia-treated and/or control mice to create four experimental F1 groups. When F1 progeny reached 15-20 wks of age, scotopic electroretinograms (ERGs) were performed at baseline, and again 7 days after 30-min of unilateral retinal ischemia.
As predicted, F1 mice derived from two normoxic F0 controls exhibited reductions in a-wave and b-wave ERG amplitudes of 38-42% (p<0.05) relative to their nonischemic eye. However, F1 mice derived from matings between hypoxic F0 fathers and nonhypoxic F0 mothers, or hypoxic F0 mothers and normoxic F0 fathers, exhibited significantly smaller reductions in waveform amplitudes of 27-32% and 20-27%, respectively, indicative of moderate neuroprotection. F1 mice derived from matings with both F0 parents hypoxic exhibited near normal ERGs (1-11% waveform amplitude reductions; p<0.0002 vs. nonhypoxic controls), reflecting virtually complete resilience to ischemic injury.
These studies document for the first time, using functional outcome measures, the epigenetic inheritance by first-generation offspring of a beneficial, retinal ischemia-protective phenotype induced only in the parental generation. The epigenetic and epidemiological implications of these Lamarckian findings for understanding, treating, and inheriting retinal health and disease are profound.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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