Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice

Abstract

SummaryGene-environment interactions are determining factors for the etiology of psychiatric disorders, diabetes and cancer, and are thought to contribute to disease inheritance across generations. Small non-coding RNAs (sncRNAs) are potential vectors at the interface between genes and environment. Here, we report that environmental conditions involving traumatic stress in early life in mice altered microRNAs (miRNAs) expression, and behavioral and metabolic responses in the progeny. Several miRNAs were affected in the serum and brain of both, the traumatized animals and their progeny when adult, but also in the sperm of traumatized males. Injection of sperm RNAs from these males into fertilized wild-type oocytes reproduced the behavioral and metabolic alterations in the resulting offspring. These results strongly suggest that sncRNAs are sensitive to environmental factors in early life, and contribute to the inheritance of trauma-induced phenotypes across generations. They may offer potential diagnostic markers for associated pathologies in humans.While the genetic make-up of an individual contributes to disease risk and heritability 1 , environmental factors, in particular, adverse and traumatic experiences in early life are also critical. How they mediate their influence is poorly understood but likely involves nongenetic mechanisms. Small non-coding RNAs (sncRNAs) are potential mediators of geneenvironment interactions that can relay signals from the environment to the genome and exert regulatory functions on gene activity 2 . They are implicated in gene dysregulation in many diseases including psychiatric and neurological conditions, cancer and metabolic disorders 2-4 . Recent studies in C. elegans 5,6 and mice 7,8 have suggested that sncRNAs can * Corresponding author: mansuy@hifo.uzh.ch. $ Current address: Neuroscience Center, University Geneva, Switzerland Authors' contribution K.G. did all RT-qPCRs, behavioral tests, metabolic measurements, sperm RNA preparation for sequencing libraries and for RNA injection into fertilized oocytes and part of the sequencing analyses. A.J. performed Western blots and cell culture experiments and assisted with metabolic measurements. J.B. carried out the MSUS procedures and produced MSUS animals. J.P. and P.S. did most RNA sequencing analyses. P.P. did the RNA injection experiments. E.M. and L.F. helped design RNA sequencing analysis. K.G. and I.M.M. designed the study, interpreted the results and wrote the manuscript.

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

“…Alternatively, intergenerational effects could result if RNAs carry sequence-specific information to gametes through circulation from distant tissues that experience chemicals, changes in diet, or stress. In support of this possibility, studies focused on intergenerational and transgenerational effects in mammals implicate RNA in the inheritance of gene expression states across generations (47), report changes in small RNAs in gametes (48,49), and report changes in RNAs acquired during gamete maturation from surrounding epithelia (50,51). However, in all these cases, direct effects of a treatment-e.g., diet-on gametes and surrounding support tissues that alter RNA composition in gametes have not been ruled out.…”

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

“…The majority of transgenerational studies have examined sperm transmission of epigenetic changes due to limitations in oocyte numbers for efficient analysis. Although DNA methylation has been investigated more extensively, noncoding RNA (ncRNA) expression has also been shown to be involved in epigenetic transgenerational inheritance [17,18]. Differentially expressed ncRNAs have been shown to correlate with increased disease susceptibility originating from the ancestrally exposed male germline [19].…”

Homage to the ‘H’ in developmental origins of health and disease

“…4,[6][7][8][9][10][11][12][13] It is also increasingly becoming apparent that the environmental state of both the mother and father can underpin later diseases in offspring, even those who appear healthy at birth. [14][15][16][17][18][19][20][21][22][23][24][25][26] Such intrinsic and extrinsic factors in animal models and humans include exposure to endocrine disrupting chemicals, such as bisphenol A, phthalates, heavy metals, stress, obesity, high fat/ high caloric diets, metabolic status and starvation conditions to provide a few examples. It is also clear that in general, males may be at greater risk for later disorders, including those of the cardiovascular and neurological systems, than females.…”