Ischemic retinopathies, including glaucoma and diabetic retinopathy, are major causes of visual morbidity and blindness. New research from Louisiana State University Health Sciences Center in New Orleans shows that an epigenetic therapy reduces retinal injury from acute ischemia, not only in the animals that receive the treatment, but also in their untreated first-generation offspring.
In a study published in the journal Investigative Ophthalmology & Visual Science, scientists treated male and female adult mice with one hour of mild-to-moderate systemic hypoxia three times per week for 16 weeks prior to mating.1 When their first-generation offspring reached adulthood, the response of their retina to transient, acute ischemic injury was functionally documented with scotopic electroretinography. Compared to age- and generation-matched controls, the ischemia-induced impairments in the retina’s response to light in the mice derived from parents that received the epigenetic hypoxia treatment was reduced by 40-50%.
“We knew from our previous work that a single exposure to systemic hypoxia would protect the adult retina from ischemia occurring one to two days thereafter, and that multiple doses over two weeks would extend that window of protection to two months,” says senior author Dr Jeff Gidday.2,3 Gidday undertook the present study with the hope of showing that the duration of the induced, injury-resilient phenotype could be extended further, perhaps even into the next generation, if treatments continued for a much longer period of time.
As with most diseases, the pathologic mechanisms involved are diverse; activating innate, counter-responses to these injury mechanisms is the conceptual basis for epigenetics-based therapeutic strategies, like intermittent hypoxia. Gidday and his team contend that systemic hypoxia triggers changes in gene expression, but that the duration of the change is largely proportional to the frequency of this epigenetic stimulus. With prolonged treatment, even germ cells become reprogrammed, resulting in progeny that, as adults, exhibit this same inducible injury-resilient phenotype in the absence of treatment.
"We exposed mice to nonharmful hypoxia to trigger these adaptive changes," says first-author Jarrod Harman, a doctoral student in Dr Gidday's lab. “But there are many epigenetic stimuli that might very well cause similar changes in gene expression, including exercise, and other 'positive' stressors. Not all stress is bad for you." These findings represent a converse example of the increase in disease susceptibility and incidence that is fairly well established to occur in progeny derived from parents repeatedly exposed to adverse, harmful stressors. To date, some rodent studies have shown that environmental enrichment can enhance baseline memory metrics in first-generation offspring, but the authors believe this is the first study to demonstrate, in mammals, that changes in the parental environment (in this case, intermittent exposure to whole-body hypoxia) can actually protect progeny against tissue injury.
The researchers also extensively analyzed the injury-resilient retinal phenotype using mass spectrometry to gain insights into the underlying mechanisms of neuroprotection. By comparing the protein profiles between mice derived from treated parents and mice derived from control parents, and then performing bioinformatic analyses of these hundreds of differentially expressed proteins, they identified dozens of biochemical pathways and networks that define the injury-resilient state. This included the reversal of a number of ischemia-induced changes in the expression of proteins and even protein subunits involved in the photoreceptor visual transduction pathway, which is responsible for the electroretinographic response to light that the authors measured as their functional metric of injury resilience. As examples, parental treatment abrogated the ischemia-induced reduction in the expression of rhodopsin by 2.5 fold, and enhanced the expression of the phosphodiesterase 6 α-subunit, and several proteins (e.g., guanylate cyclase activator 1A), responsible for generating the dark current. “Given the complexity of this intergenerational epigenetic response, using this big-data approach to illuminate the neuroprotective phenotype provides us and others a molecular foundation upon which more targeted, causal experiments can now be logically designed,” Harman says.
Overall, the findings add to our understanding of the heritability of disease – in this case, the heritability of disease resilience. "The direct inheritance of an induced, beneficial phenotype is what Lamarck famously proposed in 1809, the year Darwin was born," says Gidday. "Here we are, almost 200 years later, finding evidence to support this theory, despite it being largely displaced for the last 150 years by Darwin's Theory of Natural Selection. More than likely, both mechanisms are operative as a way to enhance both short- and long-term reproductive fitness."
1. Harman JC, Guidry JJ, Gidday JM. Intermittent hypoxia promotes functional neuroprotection from retinal ischemia in untreated first-generation offspring: Proteomic mechanistic insights. Invest Ophthalmol Vis Sci (2020). doi:https://doi.org/10.1167/iovs.61.11.15.
2. Zhu Y, Ohlemiller KK, McMahan BK, Gidday JM. Mouse models of retinal ischemic tolerance. Invest Ophthalmol Vis Sci. (2002);43(6):1903-1911.
3. Zhu Y, Zhang Y, Ojwang BA, Brantley MA Jr, Gidday JM. Long-term tolerance to retinal ischemia by repetitive hypoxic preconditioning: role of HIF-1alpha and heme oxygenase-1. Invest Ophthalmol Vis Sci. 2007;48(4):1735-1743. doi:10.1167/iovs.06-1037.