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Sperm RNA can be modified by environmental factors and has been implicated in communicating signals about changes in a father's environment to the offspring. The small RNA composition of sperm could be changed during its final stage of maturation in the epididymis by extracellular vesicles (EVs) released by epididymal cells. We studied the effect of exposure to stress in early postnatal life on the transcriptome of epididymal EVs using a mouse model of transgenerational transmission. We found that the small RNA signature of epididymal EVs, particularly miRNAs, is altered in adult males exposed to postnatal stress. In some cases, these miRNA changes correlate with differences in the expression of their target genes in sperm and zygotes generated from that sperm. These results suggest that stressful experiences in early life can have persistent biological effects on the male reproductive tract that may in part be responsible for the transmission of the effects of exposure to the offspring.

Sperm RNA can be modified by environmental factors and has been implicated in communicating signals about changes in a father’s environment to the offspring. The RNA composition of sperm is influenced during its final stage of maturation in the epididymis by extracellular vesicles released by epididymal cells. We studied the effect of exposure to stress in postnatal life on the transcriptome of epididymal extracellular vesicles using a mouse model of transgenerational transmission. We found that the small RNA signature of epididymal extracellular vesicles, particularly miRNAs, is altered in adult males exposed to postnatal stress. miRNAs changes correlate with differences in the expression of their target genes in sperm and zygotes generated from that sperm. These results suggest that stressful experiences in early life can have persistent biological effects on the male reproductive tract that may in part be responsible for the transmission of the effects of exposure to the offspring.Summary SentencemiRNA cargo of extracellular vesicles in cauda epididymis is changed by paternal exposure to early life stress, which correlates with differences in the expression of their target genes in sperm and zygotes generated from that sperm

Environmental factors can change phenotypes in exposed individuals and offspring and involve the germline, likely via biological signals in the periphery that communicate with germ cells. Here, using a mouse model of paternal exposure to traumatic stress, we identify circulating factors involving peroxisome proliferator‐activated receptor (PPAR) pathways in the effects of exposure to the germline. We show that exposure alters metabolic functions and pathways, particularly lipid‐derived metabolites, in exposed fathers and their offspring. We collected data in a human cohort exposed to childhood trauma and observed similar metabolic alterations in circulation, suggesting conserved effects. Chronic injection of serum from trauma‐exposed males into controls recapitulates metabolic phenotypes in the offspring. We identify lipid‐activated nuclear receptors PPARs as potential mediators of the effects from father to offspring. Pharmacological PPAR activation in vivo reproduces metabolic dysfunctions in the offspring and grand‐offspring of injected males and affects the sperm transcriptome in fathers and sons. In germ‐like cells in vitro, both serum and PPAR agonist induce PPAR activation. Together, these results highlight the role of circulating factors as potential communication vectors between the periphery and the germline., The EMBO Journal, 39 (23), ISSN:0261-4189, ISSN:1460-2075

Adverse experiences in early life are risk factors for the development of behavioral and physiological symptoms that can lead to psychiatric and cognitive disorders later in life. Some of these symptoms can be transmitted to the offspring, in some cases by non-genomic mechanisms involving germ cells. Using a mouse model of unpredictable maternal separation and maternal stress, we show that postnatal trauma alters coping behaviors in adverse conditions in exposed males when adult and in their adult male progeny. The behavioral changes are accompanied by increased glucocorticoid receptor (GR) expression and decreased DNA methylation of the GR promoter in the hippocampus. DNA methylation is also decreased in sperm cells of exposed males when adult. Transgenerational transmission of behavioral symptoms is prevented by paternal environmental enrichment, an effect associated with the reversal of alterations in GR gene expression and DNA methylation in the hippocampus of the male offspring. These findings highlight the influence of both negative and positive environmental factors on behavior across generations and the plasticity of the epigenome across life.

In the past decades, evidence supporting the transmission of acquired traits across generations has reshaped the field of genetics and the understanding of disease susceptibility. In humans, pioneer studies showed that exposure to famine, endocrine disruptors or trauma can affect descendants, and has led to a paradigm shift in thinking about heredity. Studies in humans have however been limited by the low number of successive generations, the different conditions that can be examined, and the lack of mechanistic insight they can provide. Animal models have been instrumental to circumvent these limitations and allowed studies on the mechanisms of inheritance of environmentally induced traits across generations in controlled and reproducible settings. However, most models available today are only intergenerational and do not demonstrate transmission beyond the direct offspring of exposed individuals. Here, we report transgenerational transmission of behavioral and metabolic phenotypes up to the 4th generation in a mouse model of paternal postnatal trauma (MSUS). Based on large animal numbers (up to 124 per group) from several independent breedings conducted 10 years apart by different experimenters, we show that depressive-like behaviors are transmitted to the offspring until the third generation, and risk-taking and glucose dysregulation until the fourth generation via males. The symptoms are consistent and reproducible, and persist with similar severity across generations. These results provide strong evidence that adverse conditions in early postnatal life can have transgenerational effects, and highlight the validity of MSUS as a solid model of transgenerational epigenetic inheritance., Environmental Epigenetics, 4 (2), ISSN:2058-5888

Traumatic stress in early-life increases the risk for cognitive and neuropsychiatric disorders later in life. Such early stress can also impact the progeny even if not directly exposed, likely through epigenetic mechanisms. Here, we report in mice that the offspring of males subjected to postnatal traumatic stress have decreased gene expression in molecular pathways necessary for neuronal signaling, and altered synaptic plasticity when adult. Long-term potentiation is abolished and long-term depression is enhanced in the hippocampus, and these defects are associated with impaired long-term memory in both the exposed fathers and their offspring. The brain-specific gamma isoform of protein kinase C (Prkcc) is one of the affected signaling components in the hippocampus. Its expression is reduced in the offspring, and DNA methylation at its promoter is altered both in the hippocampus of the offspring and the sperm of fathers. These results suggest that postnatal traumatic stress in males can affect brain plasticity and cognitive functions in the adult progeny, possibly through epigenetic alterations in the male germline.