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Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health

Key Points

  • Spermatozoa have a unique epigenetic signature, consisting of their DNA methylation profile, DNA-associated proteins, protamine 1:protamine 2 ratio, nucleosome distribution pattern, post-translational histone modifications, stored RNA and nonhistone and nonprotamine proteins

  • Dietary compounds, especially phytochemicals, minerals and vitamins, can effect changes in epigenetic signatures of somatic as well as germ cells by influencing enzymes and other proteins responsible for epigenetic modifications

  • Modifications of the epigenetic landscape by dietary compounds can affect overall health but also the reproductive health of both sexes

  • Studies in animal models and human epidemiological data point toward a transgenerational effect of parental nutrition on offspring health

  • Male germ cell development can be divided into distinct stages, each representing a time window of susceptibility to epigenetic alterations, resulting in specific epigenetic changes in descendants and their phenotypes


Epigenetic inheritance and its underlying molecular mechanisms are among the most intriguing areas of current biological and medical research. To date, studies have shown that both female and male germline development follow distinct paths of epigenetic events and both oocyte and sperm possess their own unique epigenomes. Fertilizing male and female germ cells deliver not only their haploid genomes but also their epigenomes, which contain the code for preimplantation and postimplantation reprogramming and embryonal development. For example, in spermatozoa, DNA methylation profile, DNA-associated proteins, protamine 1:protamine 2 ratio, nucleosome distribution pattern, histone modifications and other properties make up a unique epigenetic landscape. However, epigenetic factors and mechanisms possess certain plasticity and are affected by environmental conditions. Paternal and maternal lifestyle, including physical activity, nutrition and exposure to hazardous substances, can alter the epigenome and, moreover, can affect the health of their children. In male reproductive health, data are emerging on epigenetically mediated effects of a man's diet on sperm quality, for example through phytochemicals, minerals and vitamins, and nutritional support for subfertile men is already being used. In addition, studies in animal models and human epidemiological data point toward a transgenerational effect of the paternally contributed sperm epigenome on offspring health.

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Figure 1: Epigenetic processes during male germ cell development.
Figure 2: Effects of diet on the main epigenetic processes.
Figure 3: Bioactive substances that can affect enzymes involved in epigenetic processes.
Figure 4: Key epigenetic events during human development.


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The authors wish to acknowledge grant support from the German Research Foundation (DFG), Clinical Research Unit KFO181 and the University Medical Center Giessen and Marburg (UKGM; 29/2015GI).

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All authors researched data for the article, made a substantial contribution to discussion of content, wrote and reviewed and/or edited the article before submission.

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Correspondence to Klaus Steger.

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PowerPoint slides



The study of mechanisms that regulate gene expression without changing the underlying DNA sequence, for example, gene silencing through addition of methyl groups to DNA and/or to histones.


In haploid male germ cells, histones are replaced by arginine-rich proteins termed protamines, resulting in high-order nuclear chromatin compaction.

Imprinted genes

Genes that are expressed in a parent-of-origin-dependent manner depending on genomic imprinting. For example, if the paternally inherited allele is imprinted (for example, silenced due to methylated cytosines within the gene promoter) only the maternal allele is expressed.


A 147 bp DNA sequence wound around a histone octamere that consists of two molecules each of histones H2A, H2B, H3 and H4.


In repetitive DNA, short interspersed nuclear elements (SINEs, containing 100–500 bp) and long interspersed nuclear elements (LINEs, containing 6–8 kbp) make up 52% of all known repeat elements, which are mainly localized in heterochromatin.

Epigenetic tagging

Addition of methyl or acetyl groups to DNA and/or histones by specialized enzymes results in specific epigenetic signatures that can act as a 'cellular memory' when inherited by offspring.

Restriction landmark genomic scanning

A method to visualize differences in DNA methylation levels across the genome, consisting of DNA digestion by restriction enzymes followed by radioactive labelling and 2D electrophoresis.


The sum of all microorganisms hosted by an individual in an environmental niche.

One-carbon metabolism

Folate and methionine cycles constitute a one-carbon metabolism, as only one carbon group is transferred, for example, a methyl group via S-adenosylmethionine.

Polycomb group protein complexes

Cluster of proteins belonging to one family that are involved in chromatin remodelling to facilitate epigenetic gene silencing.

DNA fragmentation

A hallmark of apoptosis during which endonucleases cleave chromatin into nucleosomal units representing multiples of 180 bp.

Reactive oxygen species

Highly reactive chemical species (radicals) formed as a natural byproduct of oxygen metabolism. During oxidative stress, levels of reactive oxygen species can increase and effect cell damage.

Transgenerational epigenetics

Transmission of parental epigenetic signatures and their effects further than the first generation of children (F1 generation; classified as intergenerational epigenetics) to grandchildren and subsequent offspring (F2 and following generations).

Agouti-viable-yellow (Avy) mouse

In this model, expression of the metastable Avy allele depends on the methylation status of an intracisternal A particle located upstream of the Asip transcription start site. Low methylation levels of CpG sites result in high agouti-signalling protein expression from Asip and the agouti phenotype (yellow coat colour), whereas methylated CpG sites result in low expression levels and the pseudoagouti phenotype (brown coat colour).

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Schagdarsurengin, U., Steger, K. Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health. Nat Rev Urol 13, 584–595 (2016).

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