Poster Presentation Australasian RNA Biology and Biotechnology Association 2026 Conference

Investigating Paternal Epigenetic Inheritance via small non-coding RNA: Intergenerational effects of Paternal Immune Activation (#147)

Sonali N Reisinger 1 , Nicholas Van De Garde 1 , Pamudika Kiridena 1 , Ganani Dontamsetti 1 , Bethany A Masson 2 , Qi Meng 3 , Da Lu 1 , Huan Liao 1 , Pranav Adithya 4 , Carolina Gubert 5 , Anthony J Hannan 1 6
  1. Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
  2. Walter and Eliza Hall Institute, Parkville, VIC, Australia
  3. Department of Medicine, University of Melbourne , Parkville, VIC, Australia
  4. School of BioSciences, University of Melbourne, Parkville, VIC, Australia
  5. School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia
  6. Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, Australia

In the last decade, paternal immune activation (PIA) has emerged as a key exposure type leading to heritable epigenetic inheritance, with significant impacts on offspring phenotypes including brain development and behaviour.

Using complementary mouse models of PIA, including the administration of the cytokines tumour necrosis factor alpha (TNF-α) or interleukin 1β (IL-1β), or high molecular weight Poly I:C (polyinosinic:polycytidylic acid, a viral mimetic), to fathers 4 weeks before mating, we have started to elucidate the mechanisms underlying epigenetic inheritance after PIA.

Firstly, we administered cytokines to male mice, and found that this was sufficient to induce modifications in the small non-coding RNA (sncRNA) sperm profile of fathers, and changes in offspring brain-behavioural phenotypes. This demonstrated, for the first time, that immune molecules produced downstream of the paternal immune response may be responsible for the epigenetic inheritance observed after PIA, rather than direct effects of pathogens or pathogen mimics. 

In another study, we found that activation of the innate immune response via high molecular weight poly I:C produced changes in sperm and offspring behavioural outcomes that were distinct from those arising after stimulation by low molecular weight poly I:C. These findings suggest that the molecular structure of an immune stimulant determines how epigenetic remodelling in the sperm takes place, thereby influencing the outcomes of epigenetic inheritance after immune activation. . 
In addition, for the first time in the context of PIA, we examined how the expression of sncRNA in several somatic reproductive tissues (testes, cauda epididymis), and in mature sperm, change over time after Poly I:C administration (at 24 hours and 4 weeks post-treatment), illuminating the dynamics of epigenetic signal transduction from soma to germline in the context of PIA.

Collectively, these findings contribute to the advancement of our understanding of intergenerational effects of PIA and underscore the importance of sperm sncRNA as a determinant of offspring health which is able to respond in a highly sensitive and dynamic manner to environmental influences.