Paternal epigenetic programming: evolving metabolic disease risk

Abstract

Parental health or exposures can affect the lifetime health outcomes of offspring, independently of inherited genotypes. Such 'epigenetic' effects occur over a broad range of environmental stressors, including defects in parental metabolism. Although maternal metabolic effects are well documented, it has only recently been established that that there is also an independent paternal contribution to long-term metabolic health. Both paternal undernutrition and overnutrition can induce metabolic phenotypes in immediate offspring, and in some cases, the induced phenotype can affect multiple generations, implying inheritance of an acquired trait. The male lineage transmission of metabolic disease risk in these cases implicates a heritable factor carried by sperm. Sperm-based transmission provides a tractable system to interrogate heritable epigenetic factors influencing metabolism, and as detailed here, animal models of paternal programming have already provided some significant insights. Here, we review the evidence for paternal programming of metabolism in humans and animal models, and the available evidence on potential underlying mechanisms. Programming by paternal metabolism can be observed in multiple species across animal phyla, suggesting that this phenomenon may have a unique evolutionary significance.

Research Review: Intergenerational transmission of disadvantage: epigenetics and parents' childhoods as the first exposure

“…Given these critiques on the evidence of intergenerational epigenetic inheritance on animal studies, recent research has focused on elucidating the specific mechanisms of transmission. DNA methylation is an often‐cited candidate for transmissible epigenetic modification, given that it is stable, known to be heritable through cell division, and is retained during sperm maturation, when other epigenetic marks are largely removed (Hur, Cropley, & Suter, ). However, the biological significance of DNA methylation can be difficult to interpret, as changes are often small and widespread throughout the genome and affect a variety of genes (Carone et al., ; Soubry, ).…”

“…Given that most functional genomic elements are extensively demethylated after fertilization (Guo et al. ), there remain significant challenges to support the idea that inherited DNA methylation patterns are responsible for the transmission of programming from parent to child (Hur et al., ).…”

“…Another prominent theory for epigenetic intergenerational inheritance involves the actions of small noncoding RNA (snRNA), functional RNA molecules that are transcribed from DNA but are not translated into proteins. (Franklin et al., ; Gapp et al., ; Hur et al., ; Szyf, ). Only around 2% of genomic transcripts are translated into protein (Peschansky & Wahlestedt, ), and the remaining transcripts – which do not code for protein – were first regarded as ‘junk’.…”

Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice

“…There is growing evidence indicating paternal health and well-being at the time of conception also impacts on offspring long-term cardiometabolic health (Hur et al 2017;Lucas & Watkins, 2017). In mice, paternal undernutrition perturbs embryonic development and metabolism, fetal growth and adult offspring cardiometabolic ill-health (Carone et al 2010;McPherson et al 2016;Watkins et al 2017).…”

Grandpaternal-induced transgenerational dietary reprogramming of the unfolded protein response in skeletal muscle

“…When phenotypic changes in the first generation are similar or the same as the inducing stressor, this can, in turn, program the phenotype of the second generation by a process known as serial programming [14]. In rodents, paternal chronic exposure to low-protein diet increases the expression of hepatic genes involved in lipid and cholesterol metabolism [12].…”