Douglas M. Ruden
Environmental exposures can influence phenotypes across generations, yet the cellular routes by which somatic stress signals reach the germline remain poorly defined. piRNAs are attractive candidates for transgenerational epigenetic inheritance because they silence transposable elements, guide chromatin regulation, carry a stabilizing 3′ 2′-O-methyl modification, and participate in self-reinforcing amplification pathways, including ping-pong amplification in animals and RNA-dependent RNA polymerase (RdRP)-mediated secondary small-RNA amplification in systems such as C. elegans. This review examines evidence linking piRNAs, macrophage biology, and environmentally induced inheritance. We first summarize small-RNA inheritance in animals, plants, and ciliates, emphasizing C. elegans piRNA-triggered epigenetic memory and plant RNA-directed DNA methylation as parallel small-RNA-based inheritance systems. We then discuss emerging evidence that macrophage polarization states contain distinct piRNA signatures and release extracellular vesicles carrying non-coding RNAs. Finally, we revisit the Drosophila ectopic large bristle outgrowth (ELBO) phenotype as a possible example of macrophage-like hemocytes linking stress, tissue remodeling, and heritable morphological variation. We propose the macrophage-mediated morphological evolution (M3) model as a testable framework connecting environmental stress to transgenerational phenotypes.