Molecular mechanisms of paternal immune activation

Many mental illnesses are considered to be partially heritable, however a considerable proportion of disease risk is attributable to environmental factors. Intriguingly, increasing evidence indicates that environmental influences mayalso significantly impactthe physical andmental health of any progeny. This type of intergenerational inheritance has been proposed to be mediated by epigenetic mechanisms, which allow the transmission of traits without altering the DNA sequence of an individual. In addition to chronic stress or high-fat diet, pathogenic infections represent a key exposure type with the potential to determine offspring and grand-offspring health outcomes, including mental well-being. This aspect of intergenerational inheritance is especially salient following the global SARS-CoV-2 pandemic, where tens of millions of reproductive-aged men were infected. While this virus has already had devastating effects on human life across the world, potential effects on future generations are still unknown. The pertinent underlying mechanisms both within the parent and within the offspring need to be resolved if we aim to prevent the transmission of these pathological traits in the future. Here, a mouse model of paternal immune activation where males are exposed to a viral mimetic (polyinosinic:polycytidylic acid or Poly I:C) several weeks prior to mating, and offspring show alterations in affective behaviour as well as metabolic and immune function, will be investigated. Rodent behavioural analysis will be combined with the detailed analyses of several tissues obtained from the fathers and offspring in these experiments, including paternal sperm and relevant offspring brain areas. Using a new type of powerful statistical analysis, observed changes in offspring behaviour will be related to specific disturbances in protein and RNA levels in the collected tissues. This approach will yield new insights into the complex nature of the transmission mechanism after paternal immune activation, since it will be possible to link molecular changes correlating the most tightly with significant phenotypic changes across a multitude of tissues, thus shedding light on disrupted pathways which are most likely to be causally involved in the modulation of offspring health. This approach may be particularly appropriate, as well as insightful, when considering the main research: How do initial changes in a single cell the male gamete lead to alterations in any number of cell types or organs in the progeny? This will be the first study to employ this type of multivariate analysis, which involves the use of machine learning algorithms, in the field of intergenerational epigenetic inheritance after paternal immune activation. The insights gained from this study have the potential of uncovering an important biological mechanism, the potential significanceof which theCOVID-19pandemichashighlighted.

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