Involvement of circulating factors in the transmission of paternal experiences through the germline

Gretchen van Steenwyk

Katharina Gapp

Ali Jawaid

Pierre‐Luc Germain

Francesca Manuella

Deepak K Tanwar

Nicola Zamboni

Niharika Gaur

Anastasiia Efimova

Kristina M Thumfart

Eric A Miska

Isabelle M Mansuy

Author Information

EMBO Journal (2020)e104579


Peer Review


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.


Exposure of mice to traumatic stress in early life leads to phenotypic changes that are transmitted to the progeny via mechanisms that remain poorly characterized. In vivo and in vitro findings from mice and humans implicate serum‐induced peroxisome proliferating‐activated receptor (PPAR) signaling in transmission of environmentally‐induced paternal traits via germline.

  • Lipid metabolism pathways are altered in plasma of adult male mice exposed to postnatal trauma and their adult offspring
  • Lipid metabolism is also altered in plasma and saliva of human orphan children.
  • Serum from mice with postnatal trauma activates PPAR nuclear receptors in spermatogonial cells in vitro.
  • Pharmacological PPAR activation in vivo recapitulates trauma‐induced metabolic phenotypes in adult mice and their offspring and sperm RNA alterations in fathers.
  • Injection of serum from trauma‐exposed males into control males recapitulates metabolic symptoms in their offspring.


Environmental factors and life events can have long‐lasting consequences for exposed individuals, and in some cases, they can also impact their offspring. Transmission of environmentally induced features and diseases has been overlooked for decades. But today, evidence that diet, traumatic experiences or endocrine disruptors have effects across generations has accumulated in humans and experimental animals (Bohacek & Mansuy, 2015; Nilsson et al2018; Panzeri & Pospisilik, 2018). These effects are known to depend on epigenetic factors and constitute an important aetiological component of many diseases. When transmitted from parent to progeny and not depending on maternal care or social factors, they are thought to involve the germline. They therefore represent a form of heredity. But how exposure can affect the germline and which signals induced by exposure in the body can reach germ cells is not known. These signals may vary depending on the type of exposure, its time window, chronicity, etc. They have in common the ability to reach germ cells. Circulating factors are important vectors of communication between tissues and cells across the body. We postulate that they can carry signals induced by exposure to germ cells and contribute to the transmission of the effects of exposure to the progeny. Blood metabolites in particular are strong candidates for being such carriers because many are potent signalling molecules, e.g. hormones, lipids, organic acids and antioxidants. Further, they are dynamically regulated by physiological states in mammals. Several metabolites have been previously implicated in the epigenetic regulation of the genome in different tissues (Donohoe & Bultman, 2012; Kaelin et al2013; Sharma & Rando, 2017).

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About S. R. Zelenz 119 Articles
S.R. Zelenz has worked in education for 20 years. Working with students from all walks of life, cultures, races, and social diversity, Zelenz’s research in Educational Leadership led to finding a better way to approach learning for students with trauma histories. Many were juvenile offenders, gang members, diagnosed with varying behavioral disorders, or had family histories of violence, murder, or narcissistic parenting. This research could not be effectively accomplished without further understanding: how epigenetic trauma inheritance may be impacting these students; how brain development from trauma may be impacting their behavioral and emotional development; as well as deep understanding of psychology and its varying classifications for behavioral and personality disorders. The goal is to find solutions for changing the conversation and making a real difference for these students. She has also worked with nonprofits of varying focus areas for the last 25 years. Her undergraduate degree in Arts Administration and Music prepared her for managing nonprofits of any size as well as procuring funding so that they can achieve their goals. Pairing her nonprofit background with her education background, she has been able to make a difference for over 200 nonprofits worldwide, written curriculum for schools across the globe, and assisted many arts organizations through performance and management.