Recent studies have suggested that early-life stressors and traumatic experiences can cause heritable changes in gene expression in future generations. Researchers at the University of Zurich’s Brain Research Institute hypothesized that early-life stressors in male mice may cause heritable changes in the small, non-coding RNA content (including miRNAs) in the sperm of traumatized mice and that this may induce behavioral changes in future progeny. Using RNA-Seq, global miRNA content in male sperm of controls and a model system of males subjected to unpredictable maternal separation combined with unpredictable maternal stress (MSUS) had significantly altered expression patterns. Additionally, miRNA in the sperm of MSUS mice exhibited altered miRNA expression in the serum and hippocampus. The changes in miRNA expression were similar in the serum and the hippocampus of F2 progeny of the MSUS males compared to control. However, the miRNA expression levels in F2 sperm were similar to normal controls. Despite this, F2 and F3 progeny exhibited behavioral traits similar to those of the initial F1 MSUS fathers. The authors note that “it is possible that the changes in miRNA that initially occurred in sperm cells as a result of MSUS are transferred to other non-genomic or epigenetic marks, such as DNA methylation or histone post-modifications, for maintenance and further transmission.
Gapp et. al. investigated metabolic conditions that are commonly altered due to early-life stressors. Serum insulin and blood glucose levels were lower in F2 progeny compared to controls, despite normal levels of each observed in F1 MSUS mice. Additionally, F2 mice showed signs of hyper-metabolism and lower body weight compared to F1 MSUS mice and controls. MicroRNA 375 was found to be elevated in the sperm of F1 MSUS mice, as well as F1 serum and hippocampal tissue. F2 progeny exhibited normal miR-375 expression levels in the sperm and serum, but elevated levels in the hippocampus compared to controls. Catenin β1 (Ctnnb1), a protein involved in stress pathways and a target of miR-375, was found to be repressed in the hippocampus of F2 progeny and represents a proof-of-concept that changes in sperm miRNA content due to environmental stressors can have downstream regulatory impacts on protein expression in future generations. Intriguingly, sperm from MSUS males was injected into control mouse oocytes and the experimental mice exhibited behavioral and metabolic traits similar to those of young, control mice subjected to MSUS stress. Together these data identify a miRNA mechanism by which environmental and behavior stressors can trigger heritable changes in future progeny. Further research will be required to confirm and expand upon these results in order to identify additional, novel miRNA mechanisms that contribute to this process.
Gapp K, Jawaid A, Sarkies P, Bohacek J, Pelczar P, Prados J, Farinelli L, Miska E, Mansuy IM. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci. 2014 May;17(5):667-9. doi: 10.1038/nn.3695. Epub 2014 Apr 13. PubMed PMID: 24728267.
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