Review
Diet-Induced Modification of the Sperm Epigenome Programs Metabolism and Behavior

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Highlights

  • Epigenetic programming is a meaningful nongenetic process for conveying information from one generation to the next. However, paternal epigenetic inheritance has received scant attention.

  • Paternal obesity, as a result of an excessive consumption of calorie dense, poor-quality foods, can predict adverse health consequences for the offspring.

  • Rodent models of obesity have revealed diet-induced alterations in sperm and seminal plasma that represent paternal transmission of epigenetic markers. These may influence the development, behavior, and brain function of the offspring. In particular, sperm small and long noncoding RNAs appear to be prime candidates for mediating dietary effects through the paternal line.

  • Further research will be necessary to define the mechanisms underlying diet-induced alterations in paternal sperm and offspring phenotype.

Globally, obesity has reached epidemic proportions. The rapidly increasing numbers of overweight people can be traced back to overconsumption of energy-dense, poor-quality foods as well as physical inactivity. This development has far-reaching and costly implications. Not only is obesity associated with serious physiological and psychological complications, but mounting evidence also indicates a ripple effect through generations via epigenetic changes. Parental obesity could induce intergenerational and transgenerational changes in metabolic and brain function of the offspring. Most research has focused on maternal epigenetic and gestational effects; however, paternal contributions are likely to be substantial. We focus on the latest advances in understanding the mechanisms of epigenetic inheritance of obesity-evoked metabolic and neurobiological changes through the paternal germline that predict wide-ranging consequences for the following generation(s).

Section snippets

Junk Food, the Obesity Epidemic, and Transgenerational Effects of Diet

Unhealthy diets can have negative long-term consequences on subsequent generations. This alarming conclusion is largely the result of recent transgenerational studies in rodents [1,2]. This finding has particular translational relevance to humans because obesity (see Glossary) in youth and adults of child-bearing age is dramatically increasing [3]. Globally, the number of obese children has risen tenfold in the past four decades [4]. Childhood obesity, especially during puberty, is associated

How Paternal Diet and Obesity Physiologically Impact on the Metabolic Profiles of Offspring

Recent findings from human and rodent studies indicate that the periconceptional phase, encompassing the stages of gamete maturation, fertilization, and early embryogenesis, is particularly sensitive to environmental influences, including unhealthy high-fat diets (HFDs) [15]. Hence, external stimuli may be capable of causing long-term phenotypic changes through epigenetic, cellular, and physiological mechanisms following either perturbation or adaptive responses [16].

HFD feeding of male mice

From Mice to Men – What We Can Learn from Rodent Models of Obesity

Because human studies can be highly confounded by lifestyle factors such as smoking and activity levels [22], animal models have been instrumental in circumventing these limitations and to examine the specific effects of paternal dietary patterns. In rodent models, obesity can be generated by providing diets with a high proportion of saturated fats, sugars, or both. Feeding male mice a HFD has been associated with obesity-related metabolic phenotypes such as glucose intolerance and insulin

Influence of Diet and Obesity on the Sperm Epigenome and Epigenetic Inheritance

The sperm epigenome has recently started to draw increasing attention in terms of its contribution to embryo development [46]. The previous underappreciation was based on the fact that during spermiogenesis the majority of nucleosomes – as well as most epigenetic information – is removed and replaced by small basic proteins, called protamines, resulting in a highly compact genome that is essential for fertility and genome integrity [46]. An obesogenic diet has been associated with alterations

Nongenetic Effects of Paternal Diet and Obesity on Progeny

Because alterations to sperm and seminal plasma are indeed capable of influencing the developing organism from as early as the stage of fertilization, the question arises of how these affect the progeny in the short- and long-term. An increasing number of studies indicate paternally transmitted effects of a poor-quality diet on early developmental, metabolic, and behavioral parameters (Figure 2 and Table 2).

Concluding Remarks and Future Perspectives

Most studies to date have focused on the impact of either high-fat or high-sugar diets on metabolic, physiologic, and psychiatric parameters. However, disentangling the effects of single macronutrients to study the relationship between diet and disease is not currently feasible, which is why a comprehensive analysis of the combined effects of HFHS diets would be of greater significance. It has been shown that other forms of suboptimal paternal nutrition can have deleterious effects on the

Acknowledgments

A.C.R. receives funding from a Canada First Research Excellent Fund BrainsCAN Senior Fellowship. A.J.H. is a National Health and Medical Research Council (NHMRC) Principal Research Fellow and is also supported by NHMRC Project Grants and the DHB Foundation Equity Trustees. This work was funded by an Australian Research Council (ARC) Discovery Project grant (DP180101974 to A.C.R. and A.J.H.). The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the

Glossary

Blood–brain barrier
a selective barrier formed from endothelial cells adjoined with tight junctions that allows specific molecules from the blood to permeate by either diffusion or active transport through into the cerebral vasculature or cerebrospinal fluid.
Blood–testis barrier
a protective semipermeable barrier, similar to that of the blood–brain barrier, between blood vessels and the seminiferous tubules where spermatozoa are generated.
Epigenetics
structural adaptation of chromosomal regions

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