Rahia Mashoodh

Epigenetics and the Origins of Paternal Effects

Though there are multiple routes through which parents can influence their offspring, recent studies of environmentally induced epigenetic variation have highlighted the role of non-genomic pathways. In addition to the experience-dependent modification of DNA methylation that can be achieved via mother-infant interactions, there has been increasing interest in the epigenetic mechanisms through which paternal influences on offspring development can be achieved. Epidemiological and laboratory studies suggest that paternal nutritional and toxicological exposures as well as paternal age and phenotypic variation can lead to variations in offspring and, in some cases, grand-offspring development. These findings suggest a potential epigenetic germline inheritance of paternal effects. However, it may be important to consider the interplay between maternal and paternal influences as well as the experimental dissociation between experience-dependent and germline transmission when exploring the role of epigenetic variation within the germline as a mediator of these effects. In this review, we will explore these issues, with a particular focus on the potential role of paternally induced maternal investment, highlight the literature illustrating the transgenerational impact of paternal experiences, and discuss the evidence supporting the role of epigenetic mechanisms in maintaining paternal effects both within and across generations.

Social influences on neurobiology and behavior: Epigenetic effects during development

The quality of the social environment can have profound influences on the development and activity of neural systems with implications for numerous behavioral and physiological responses, including the expression of emotionality. Though social experiences occurring early in development may be particularly influential on the developing brain, there is continued plasticity within these neural circuits amongst juveniles and into early adulthood. In this review, we explore the evidence derived from studies in rodents which illustrates the social modulation during development of neural systems, with a particular emphasis on those systems in which a long-term effect is observed. One possible explanation for the persistence of dynamic changes in these systems in response to the environment is the involvement of epigenetic mechanisms, and here we discuss recent studies which support the role of these mechanisms in mediating the link between social experiences, gene expression, neurobiological changes, and behavioral variation. This literature raises critical questions about the interaction between neural systems, the concordance between neural and behavioral changes, sexual dimorphism in effects, the importance of considering individual differences in response to the social environment, and the potential of an epigenetic perspective in advancing our understanding of the pathways leading to variations in mental health.

Paternal social enrichment effects on maternal behavior and offspring growth

Paternal environmental experiences are significant predictors of developmental outcomes in offspring and can occur even in the absence of paternal care. Although there has been a recent focus on the role of environmentally induced changes in the male germline in producing these effects, the potential mediating role of mothers has not been investigated. A role for mothers in the transmission of paternal effects has been well acknowledged in behavioral ecology, which predicts that females will dynamically adjust their reproductive investment in response to the qualities of their mate. In the present study, we show that a lifetime of socially enriched compared with impoverished housing conditions shifts anxiety-like behavior and gene expression of male mice. Females that mate with enriched-reared males exhibit increased levels of pup nursing and licking toward their offspring, which are associated with changes in gene expression within the maternal hypothalamus. Significantly, these changes in maternal behavior are correlated with the general levels of anxiety exhibited by their male mates. Further, we show that paternal environmental enrichment results in increased growth of their offspring. These results suggest that maternal–paternal interactions at mating may guide offspring development, with significant implications for the transgenerational transmission of paternal environmental experiences.

Parent-of-origin and trans-generational germline influences on behavioral development: the interacting roles of mothers, fathers, and grandparents.

Mothers and fathers do not contribute equally to the development of their offspring. In addition to the differential investment of mothers versus fathers in the rearing of offspring, there are also a number of germline factors that are transmitted unequally from one parent or the other that contribute significantly to offspring development. This article shall review four major sources of such parent-of-origin effects. Firstly, there is increasing evidence that genes inherited on the sex chromosomes including the nonpseudoautosomal part of the Y chromosome that is only inherited from fathers to sons, contribute to brain development and behavior independently of the organizing effects of sex hormones. Secondly, recent work has demonstrated that mitochondrial DNA that is primarily inherited only from mothers may play a much greater than anticipated role in neurobehavioral development. Thirdly, there exists a class of genes known as imprinted genes that are epigenetically silenced when passed on in a parent-of-origin specific manner and have been shown to regulate brain development and a variety of behaviors. Finally, there is converging evidence from several disciplines that environmental variations experienced by mothers and fathers may lead to plasticity in the development and behavior of offspring and that this phenotypic inheritance can be solely transmitted through the germline. Mechanistically, this may be achieved through altered programming within germ cells of the epigenetic status of particular genes such as retrotransposons and imprinted genes or potentially through altered expression of RNAs within gametes.

Genes in Context Gene–Environment Interplay and the Origins of Individual Differences in Behavior

Interactions between genes and the environment are a critical feature of development. Insights into the dynamic interplay between these factors have come from laboratory studies exploring experience-dependent changes in gene function, which illustrate the importance of environmental factors in determining activity of the genome. These studies have implications for our understanding of the origins of individual differences in behavior and may provide new ways of thinking about the transmission of traits across generations. Here we will highlight how these new findings illustrate the importance of putting genes in context.

Concordance in hippocampal and fecal Nr3c1 methylation is moderated by maternal behavior in the mouse.

Recent advances in genomic technologies now enable a reunion of molecular and evolutionary biology. Researchers investigating naturally living animal populations are thus increasingly able to capitalize upon genomic technologies to connect molecular findings with multiple levels of biological organization. Using this vertical approach in the laboratory, epigenetic gene regulation has emerged as an important mechanism integrating genotype and phenotype. To connect phenotype to population fitness, however, this same vertical approach must now be applied to naturally living populations. A major obstacle to studying epigenetics in noninvasive samples is tissue specificity of epigenetic marks. Here, using the mouse as a proof-of-principle model, we present the first known attempt to validate an epigenetic assay for use in noninvasive samples. Specifically, we compare DNA methylation of the NGFI-A (nerve growth factor-inducible protein A) binding site in the promoter of the glucocorticoid receptor (Nr3c1) gene between central (hippocampal) and peripheral noninvasive (fecal) tissues in juvenile Balb/c mice that had received varying levels of postnatal maternal care. Our results indicate that while hippocampal DNA methylation profiles correspond to maternal behavior, fecal DNA methylation levels do not. Moreover, concordance in methylation levels between these tissues within individuals only emerges after accounting for the effects of postnatal maternal care. Thus, although these findings may be specific to the Nr3c1 gene, we urge caution when interpreting DNA methylation patterns from noninvasive tissues, and offer suggestions for further research in this field.

Maternal modulation of paternal effects on offspring development

The paternal transmission of environmentally induced phenotypes across generations has been reported to occur following a number of qualitatively different exposures and appear to be driven, at least in part, by epigenetic factors that are inherited via the sperm. However, previous studies of paternal germline transmission have not addressed the role of mothers in the propagation of paternal effects to offspring. We hypothesized that paternal exposure to nutritional restriction would impact male mate quality and subsequent maternal reproductive investment with consequences for the transmission of paternal germline effects. In the current report, using embryo transfer in mice, we demonstrate that sperm factors in adult food restricted males can influence growth rate, hypothalamic gene expression and behaviour in female offspring. However, under natural mating conditions females mated with food restricted males show increased pre- and postnatal care, and phenotypic outcomes observed during embryo transfer conditions are absent or reversed. We demonstrate that these compensatory changes in maternal investment are associated with a reduced mate preference for food restricted males and elevated gene expression within the maternal hypothalamus. Therefore, paternal experience can influence offspring development via germline inheritance, but mothers can serve as a modulating factor in determining the impact of paternal influences on offspring development.

Paternal Epigenetic Inheritance

Abstract Paternal experiences (i.e. nutritional, hormonal, toxins, social, stress) can induce significant variation in phenotype and these effects can persist across generations. Investigations of the mechanistic pathways linking paternal experience to offspring and grand-offspring outcomes have implicated epigenetic modifications as a plausible route through which these effects are achieved. Within this framework, environmentally induced epigenetic variation occurs in male gametes is maintained following post-fertilization epigenetic reprogramming, alters gene activity and phenotype in offspring, and is transmitted to subsequent generations via the germline. There is increasing evidence in support of this hypothesized epigenetic inheritance and here we discuss the potential role of altered DNA methylation, post-translational histone modifications, and small RNAs in these transgenerational effects. However, within our expanding understanding of the mechanisms of paternal effects, it is important to incorporate a more inclusive notion of inheritance that includes genetic, epigenetic, and paternal–maternal interplay. In this chapter, the authors discuss the role of these factors in the transmission of paternal effects and consider the adaptive consequence of inherited environmentally induced phenotypes.

Transgenerational Inheritance in Mammals

Transgenerational effects of exposure to environmental factors are increasingly evident, and have raised the hypothesis that environmentally-induced phenotypes can be heritable. Recent exploration of the potential implication of non-genetic processes in this inheritance has suggested that epigenetic mechanisms such as DNA methylation and microRNAs are likely involved. This chapter highlights evidence for the transmission of the effect of maternal and paternal exposure to environmental factors in mammals. It focuses on the distinction between experience-dependent and germline mechanisms of epigenetic transmission and describes the interaction between these routes of inheritance in the prediction of outcomes in the offspring.

Chapter 24 – Transgenerational Epigenetics

Publisher Summary This chapter discusses the evidence of maternal and paternal epigenetic influence on offspring development, with particular focus on studies indicating an association between parental experiences/ environmental exposures and epigenetic alterations in offspring. The role of epigenetic mechanisms in mediating the long-term effects of environmental experiences is a rapidly expanding field of study, and it has become evident that experiences across the lifespan can induce modifications to the epigenome. Moreover, these epigenetic effects can have implications for neurobiology, physiology, and behavior of an organism leading to divergent developmental outcomes. Thus the molecular mechanisms that regulate gene expression can contribute to the “epigenesis” of phenotype, in which the term “epigenetics” has its roots. Within the study of mammalian development, the quality of interactions between parents and offspring is a particularly salient aspect of the early environment and there is converging evidence from numerous experimental paradigms for parental influences on the regulation of gene expression and behavior. Though maternal effects have been well established in the literature, there is increasing evidence for paternal regulation of offspring development.