Paternal immune activation-induced alteration of 28S rRNA-derived small RNAs in sperm reprograms offspring phenotypes

TL;DR

This study shows that immune activation in fathers can alter RNA in sperm, leading to health issues in offspring like obesity and anxiety.

Contribution

The study identifies 28S rRNA-derived small RNAs in sperm as novel mediators of transgenerational effects from paternal immune activation.

Findings

Immune activation increases 28S-rsRNA levels in sperm in a time-dependent manner.

Injecting synthetic 28S-rsRNAs into zygotes reproduces metabolic and behavioral issues in offspring.

Altered 28S-rsRNAs are linked to hippocampal transcriptomic changes and anxiety-like behaviors.

Abstract

Parental environmental exposures can induce transgenerational effects through epigenetic modifications in germ cells. Although paternal immune activation is implicated in transgenerational metabolic and neuropsychiatric disorders, the germline-encoded molecular vectors mediating this inheritance remain poorly understood. Here, we demonstrated that lipopolysaccharide-induced immune activation dynamically upregulated the abundance of 28S ribosomal RNA-derived small RNAs (28S-rsRNAs) in mouse sperm in a time-dependent manner. Furthermore, epididymal sperm maturation exhibited heightened susceptibility to acute immune perturbations compared with spermatogenic processes, and 28S-rsRNAs were selectively incorporated during their transit through the caput epididymis. Strikingly, zygotic microinjection of synthetic 28S-rsRNAs recapitulated paternal immune activation phenotypes, resulting in offspring exhibiting metabolic syndrome-like phenotypes, including obesity and impaired insulin sensitivity. Concurrently, these manipulated offspring displayed neurobehavioral abnormalities characterized by heightened anxiety-like and aggressive behaviors, accompanied by hippocampal transcriptomic alterations. Taken together, our findings demonstrate that sperm 28S-rsRNAs contribute to paternal immune activation-mediated programming of offspring behavioral and metabolic phenotypes and provide mechanistic insights into environment-germline interactions.

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