Summary: Researchers conduct the first study to use nonharmful stress, like intermittent systemic hypoxia, to protect against disease in the first generation offspring in mice.
Research led by Jeff Gidday, PhD, Professor of Ophthalmology, Biochemistry, Neuroscience, and Physiology at LSU Health New Orleans School of Medicine, reports what is believed to be the first study in a mammalian model documenting the reprogramming of heritability to promote disease resilience in the next generation. The results are published in the Journal of Investigative Ophthalmology & Visual Sciencesa.
The researchers used a functional measurement to document resilience to injury of the retina of adult mice that were born to parents who were exposed to intermittent, mild systemic hypoxia (reduced concentrations of oxygen) for several months prior to mating, even though the injury-protected mice received no treatment themselves.
The therapy, akin to brief exposures to high-altitude air, is considered “epigenetic” because it modifies which genes are converted into proteins in tissues throughout the body, including germ cells (sperm and eggs).
“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 could cause these changes as well, including exercise, and other ‘positive’ stressors. Not all stress is bad for you.”
The researchers also extensively analyzed the injury-resilient retinae. By comparing the protein profiles of these retinae to those of mice derived from untreated parents using mass spectrometry, they identified many of the potential proteins and related biochemical mechanisms by which this intergenerational, injury-resilient state is achieved.
These proteins, serving in both functional and structural roles, represent potential therapeutic targets for drug development to protect against retinal diseases associated with an inadequate blood supply (ischemic retinopathies).
Other studies have shown that repetitive exposure to adverse stimuli can enhance the susceptibility of first-generation offspring to disease. But Gidday contends that, conversely, this is the first study to use a mild, nonharmful stress like intermittent systemic hypoxia to provide protection against disease in first-generation offspring.
“Research has shown that environmental enrichment can enhance some baseline memory metrics in both parents and offspring,” Gidday says, “but no study has ever shown that offspring can inherit a neuroprotective phenotype induced in parents by epigenetics. The implications of this finding with respect to our understanding of the heritability of disease susceptibility, and disease resilience, is profound.”
Companion studies addressing the safety profile of the treatment showed that the intermittently reduced oxygen stimulus used to trigger injury resilience across generations caused no injury to the most oxygen-sensitive cells of the brains of mice receiving the treatment, nor affected the normal structure or function of the retina of the adult offspring derived from treated mice.
Ischemic retinopathies are diseases that result from some degree of prolonged, lower-than-normal blood flow to the retina, compromising the delivery of much-needed oxygen and glucose to this very metabolically active tissue. The most well-known examples are glaucoma and diabetic retinopathy, but the retina can also be deprived of blood flow acutely, as happens with a heart attack or stroke. Collectively, the resultant visual impairment suffered by those with these retinopathies is staggering, and in a large percentage of cases, complete blindness can ensue.
“The direct inheritance of an induced 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 concept, despite it being largely displaced for the last 150 years by Darwin’s Theory of Natural Selection. More than likely both operate under distinct environmental situations to enhance both short- and long-term reproductive fitness.”
Funding: The research was supported by grants from the National Eye Institute of the National
Institutes of Health and Sigma Xi, as well as funding from the Louisiana Lions Eye Foundation.
About this genetics research article
Source: LSU Contacts: Leslie Capo – LSU Image Source: The image is in the public domain.
Intermittent Hypoxia Promotes Functional Neuroprotection from Retinal Ischemia in Untreated First-Generation Offspring: Proteomic Mechanistic Insights
Purpose: Stress can lead to short- or long-term changes in phenotype. Accumulating evidence also supports the transmission of maladaptive phenotypes, induced by adverse stressors, through the germline to manifest in subsequent generations, providing a novel mechanistic basis for the heritability of disease. In the present study in mice, we tested the hypothesis that repeated presentations of a nonharmful conditioning stress, demonstrated previously to protect against retinal ischemia, will also provide ischemic protection in the retinae of their untreated, first-generation (F1) adult offspring.
Methods: Swiss–Webster ND4 outbred mice were mated following a 16-week period of brief, every-other-day conditioning exposures to mild systemic hypoxia (repetitive hypoxic conditioning, RHC). Retinae of their 5-month-old F1 progeny were subjected to unilateral ischemia. Scotopic electroretinography quantified postischemic outcomes. The injury-resilient retinal proteome was revealed by quantitative mass spectrometry, and bioinformatic analyses identified the biochemical pathways and networks in which these differentially expressed proteins operate.
Results: Significant resilience to injury in both sexes was documented in F1 mice derived from RHC-treated parents, relative to matched F1 adult progeny derived from normoxic control parents. Ischemia-induced increases and decreases in the expression of many visual transduction proteins that are integral to photoreceptor function were abrogated by parental RHC, providing a molecular basis for the observed functional protection.
Conclusions: Our proteomic analyses provided mechanistic insights into the molecular manifestation of the inherited, injury-resilient phenotype. To our knowledge, this is the first study in a mammalian model documenting the reprogramming of heritability to promote disease resilience in the next generation.