Paternal bloodlines sculpting seminal concepts: circulating factors as mediators of transgenerational 'epigenopathy' and 'epigenetic resilience'

Accumulating evidence, particularly from rodent and human studies, shows that the environmental exposures and experience of a father prior to conception can modulate sperm epigenetics and subsequent offspring phenotypes. In this issue of The EMBO Journal, van Steenwyk and colleagues (2020) provide important new insights into how one form of paternal experience (early‐life stress or trauma) may impact sperm epigenetics via circulating factors, presenting novel experimental evidence from a mouse model and an analogous human cohort.

A new study identifies the role of serum factors in intergenerational transmission of paternal experiences.

The cumulative evidence that increased paternal exposure to stress, associated with elevated stress hormone levels, prior to conception can alter sperm epigenetics and offspring phenotypes has been demonstrated across multiple animal models and supported by human data (Bale, 2015; Bohacek & Mansuy, 2015; Yeshurun & Hannan, 2019). Some aspects of the mechanisms whereby stress exposures modulate sperm epigenetics have begun to be elucidated. For example, using a different paternal stress model, involving chronic stress (Rodgers et al, 2013), reproductive tract extracellular vesicles have recently been shown to transmit stress signals to male germ cells, associated with modulation of offspring neurodevelopment (Chan et al, 2020).

The new study (van Steenwyk et al, 2020) follows up this group’s previous work on an early‐life trauma model involving unpredictable maternal separation combined with unpredictable maternal stress (MSUS), with male mice exposed to this early‐life stress (versus non‐stressed controls) used for studies of paternally modulated sperm epigenetics and offspring phenotypes (Franklin et al, 2010; Gapp et al, 2014; van Steenwyk et al, 2018). These investigators identified specific factors in the circulation, involving peroxisome proliferator‐activated receptor (PPAR) pathways, as mediating the impacts of early‐life trauma on male germ cells (van Steenwyk et al, 2020). In particular, they provide evidence for lipid‐derived metabolites as mediators that transfer information from the circulation to male germ cells, and consequently modulate offspring and grand‐offspring phenotypes (i.e. the effects observed went beyond intergenerational, to transgenerational, inheritance).

In this study, the investigators also provided causal evidence supporting this proposed role of circulatory factors, via chronic injection of serum from males exposed to MSUS, which was found to recapitulate the metabolic phenotype observed in the offspring of MSUS fathers (van Steenwyk et al, 2020). Furthermore, these investigators obtained samples from a cohort of humans exposed to severe childhood trauma (which included paternal loss and maternal separation), and matched controls, and reported concordance with at least some of the metabolic alterations in the circulation of the mice exposed to MSUS (van Steenwyk et al, 2020).

These new findings (van Steenwyk et al, 2020) have important implications for this field of paternal epigenetic inheritance. In identifying circulating factors associated with early‐life paternal stress exposure, and showing causative impacts on offspring, it raises the possibility that this could be used to identify future biomarkers. This recent study also raises many new questions and draws attention to outstanding questions in this field. For example, how does early‐life stress change these circulatory factors in later life? How do the circulatory factors impact on the epigenetics of male germ cells, and sperm in particular? How does this non‐genetic (most likely epigenetic) information from male mice exposed to early‐life stress modulate the development and adult phenotype of their offspring (and grand‐offspring)? Do the parallel findings on circulatory factors in the human cohort have similar impacts on their germ cells, particularly their sperm, and their offspring? It is hoped that these key questions relating to this mouse model, and other complementary animal models, can be urgently addressed in the near future. However, the questions regarding the human correlates of the various findings in animal models require the establishment of cohort studies, with associated long‐term funding, that allow the nature (and nurture!) of intergenerational epigenetic inheritance in humans to be definitively addressed. Addressing transgenerational epigenetic inheritance (transmission through to offspring then grand‐offspring) in humans will be an even greater challenge for 21^st century science, with particular relevance to health and medical research.

The collective evidence regarding transgenerational epigenetic inheritance also has broader implications for biology, including biomedical and evolutionary aspects, and suggests that there may be extraordinary elements of Lamarckian evolution, via transgenerational epigenetic inheritance, overlayed on Darwinian evolution (genetic variation and natural selection). One further implication of this work on intergenerational epigenetic inheritance is that other environmental exposures, such as infection, of fathers prior to conception could alter their sperm epigenetics and thus the phenotypes of their offspring. In support of this hypothesis in the context of infectious disease, it has recently been discovered that infection of male mice with a pathogen (the common human parasite Toxoplasma) not only altered the levels of particular small non‐coding RNAs in their sperm, but also modulated the offspring phenotype, including behaviour, and these sperm RNAs were shown to be involved in this intergenerational epigenetic inheritance (Tyebji et al, 2020). Furthermore, it is well established that maternal immune activation (MIA), via viral infection or other stimuli, can modulate offspring phenotypes (Meyer, 2019).

An additional general implication of paternal epigenetic inheritance of acquired traits is that it may be one way that 'epigenopathy', or epigenetic contributions to disease, could be manifested. This new study (van Steenwyk et al, 2020) suggests that biomarkers of interest may include circulating factors; however, there are many other biomarkers, including sperm non‐coding RNAs, of interest. A further corollary of such studies is that nurturing environments and positive experiences could contribute to 'epigenetic resilience' (Yeshurun & Hannan, 2019). It is possible that such intergenerational information, transmitted via epigenetic mechanisms, has the potential to make an individual either more susceptible or more resilient to a given disorder. Thus, epigenopathy and epigenetic resilience may constitute 'two sides of the same coin'. Important research priorities therefore include trying to understand what aspects of the envirome (an individual’s total environmental exposures and experience throughout their lifetime) prior to conception might modulate epigenetic inheritance, and which particular exposures and experiences lead to epigenopathy versus epigenetic resilience (Fig 1).

Figure 1. The diagram illustrates key aspects of intergenerational epigenetic inheritance induced by preconceptual paternal exposures and experience.

Increasing evidence from animal models, and limited data from human studies, suggests that environmental factors (such as exposure to stress or trauma) can affect male germ cells and thus alter sperm epigenetics. Van Steenwyk et al(2020) provide new evidence that early‐life stress/trauma may alter the male germline via circulatory factors, via mechanistic data in a mouse model and correlated biomarkers in an analogous human cohort. At conception, genetic and epigenetic information in the father (F0 male) is combined with genetic and epigenetic information of the mother (F0 female) to mediate and modulate the development, structure and function of the F1 offspring. Depending on the nature of the environmental exposures and experience, the parental epigenetic information could either increase ('epigenopathy') or decrease ('epigenetic resilience') risk for a particular disorder.

It is therefore imperative that we understand the full extent to which paternal (and maternal) environmental exposures and experience may sculpt the epigenetics of human germ cells and thus increase predisposition (or resilience) to epigenopathy in the next generation. We need to find ways to improve paternal and maternal health as part of a long‐term public health approach to improving the health of offspring, keeping in mind the developmental origins of health and disease (DOHaD) and associated conceptual frameworks. A deeper understanding of mechanisms mediating transgenerational epigenetic inheritance, and thus modulating health and disease states, may facilitate new approaches to prevent, treat and eventually cure a wide range of human disorders.

The EMBO Journal (2020) 39: e107014.