The intergenerational and transgenerational effects of miRNAs in fertility, obesity and stress responses

Abstract MicroRNAs (miRNAs) are key post-transcriptional regulators that play pivotal roles in diverse physiological and pathological processes. They primarily act by inhibiting protein translation and promoting degradation of messenger RNA (mRNA), thereby inducing post-transcriptional regulatory effects. Most miRNAs can travel through blood, in extracellular vesicles, and between maternal and fetal tissues. When altered miRNAs were present in germ cells, this induces epigenetic inheritance, which influences embryonic development after fertilization. Aberrant miRNA expression is associated with a wide range of human diseases. This review article will summarize current evidence on how miRNA dysregulation contributes to transgenerational effects on reproduction, metabolism, and stress-related phenotypes. This research focuses on the impacts of miRNAs on reproductive impairment, obesity, and stress-related phenotypes, and highlights evidence that these epigenetic changes can persist across multiple generations. Relevant studies were identified mainly through PubMed database using “miRNA” and “transgenerational effect”, with a third keyword according to the topic of interest, including “reproduction”, “hormones”, “spermatogenesis”, “obesity”, “high-fat diet”, “diabetes”, “stress”, and “therapy”. In reproduction, environmental pollutants (including endocrine disruptors) can alter miRNA expression, impairing gonadal development, reducing primordial germ cells, inducing granulosa cell apoptosis, and disrupting sex hormone synthesis. miRNA-dependent pathways also affect spermatogenesis, sperm function, and oocyte development. In obesity, miRNAs regulate adipogenesis by modulating signaling pathways and transcription programs that control fat-cell formation. Paternal high-fat diet and gestational diabetes can shift miRNA profiles, raising offspring risk for obesity and metabolic disease. Chronic stress changes miRNA expression in germ cells and embryos, shaping stress reactivity and social behavior in later generations. Prenatal maternal stress is linked to lasting psychiatric vulnerability in offspring, with effects potentially persisting across multiple generations without continued stress. Overall, miRNA dysregulation can impair reproduction, metabolism, and stress responses, and these effects may be transmitted transgenerationally via epigenetic mechanisms.