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2026

Nature - Molecular Psychiatry 2026 Jun 19. doi: 10.1038/s41380-026-03674-5.

Paternal cytokine administration alters sperm small ncRNAs and offspring brain and behavior

Pamudika Kiridena, Nicholas van de Garde, Bethany A Masson, Carolina Gubert, Sonali N Reisinger Anthony J Hannan

Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia. Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia. Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia. Department of Biochemistry & Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Australia. Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia. Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia. Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, Australia.

Service type: Stock strains

Abstract

Paternal pre-conceptual exposure to pathogenic infection can alter offspring phenotypes via changes to sperm epigenetics, including small non-coding RNAs (ncRNAs). This phenomenon occurs even in the absence of infection when pathogen mimetics trigger paternal immune activation (PIA). While this implicates a shared component of the immune response, the specific mechanisms responsible remain unknown. Cytokines are a key component of innate immunity and are highly upregulated following exposure to both pathogens and their mimetics. Here we investigate whether paternal administration of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) recapitulates alterations to sperm small ncRNAs and offspring phenotypic changes from other models of PIA. C57BL/6J male mice were administered a single dose of IL-1β, TNF-α, or vehicle, prior to mating with naïve female mice, to produce offspring. Offspring from IL-1β-treated fathers exhibited altered fasting responses and female-specific alterations to stress-coping behavior. In response to paternal TNF-α, male offspring showed increased anxiety-like behavior. Analysis of paternal sperm small ncRNA revealed that IL-1β significantly downregulated several transfer RNA-derived small RNAs (tsRNAs) and P-element-induced wimpy testis (PIWI)-interacting RNA (piRNA) clusters. Surprisingly, paternal TNF-α only slightly altered small ncRNAs, downregulating a single piRNA cluster. These results partially recapitulate offspring phenotypic changes following paternal exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, in a COVID-19 mouse model) and polyinosinic:polycytidylic acid (poly I:C, a viral mimetic). Ultimately, we provide the first evidence that cytokines have intergenerational effects on brain and behavior, and that they contribute to altered offspring phenotypes in viral-like PIA. This study demonstrates that paternal cytokines are causally involved in a mechanism of epigenetic inheritance following PIA, and highlights the importance of PIA as a pre-conceptual factor that may modulate offspring health, including risk of neuropsychiatric disorders.