Paternal Diet and Epigenetic Programming of Offspring Health

Paternal nutritional status prior to conception is increasingly recognised as a determinant of offspring health through epigenetic mechanisms. Dietary macronutrient composition, energy intake and micronutrient availability can alter the epigenetic landscape of sperm—including DNA methylation, histone modifications and small RNA payload—thereby influencing early embryonic development, organogenesis and lifelong metabolic and behavioural trajectories. Evidence from animal models demonstrates that both over-nutrition and under-nutrition in fathers affect offspring adiposity, glucose regulation, stress-related behaviour and organ function in a sex-specific manner. Emerging human studies reveal associations between paternal body mass index or dietary exposures and methylation changes at imprinted loci in sperm, suggesting translatability to public health. This field highlights critical windows of germ cell susceptibility, underscores intergenerational transmission of disease risk and points to preconception dietary interventions as a means to optimise population health across generations.

Research from Nature Portfolio

Recent work has applied a nutritional geometry framework in mouse models to dissect how specific macronutrient ratios and total energy intake prior to mating shape offspring phenotype. Male mice fed diets varying in protein, carbohydrate and fat proportions sired offspring in which adiposity, metabolic markers and anxiety-like behaviours differed according to paternal dietary balance rather than simple caloric excess or restriction. Separately, models of paternal under-nutrition have shown that restricted food intake induces oxidative sperm DNA lesions and alters global methylation, leading to offspring with reduced early growth yet paradoxically increased adiposity and dyslipidaemia. Crucially, supplementing under-nourished fathers with antioxidants and vitamins restored sperm integrity and prevented adverse metabolic outcomes in their progeny, demonstrating that micronutrient fortification during the preconception period can mitigate epigenetic programming of disease.

Paternal Diet and Epigenetic Programming of Offspring Health publication trend

The graph below shows the total number of articles in paternal diet and epigenetic programming of offspring health across all publications each year (not limited to Nature Index journals).

Technical terms

Epigenetic programming: Stable alteration of gene expression potential without changes to DNA sequence, often through chemical modifications of DNA or histones.

DNA methylation: Addition of methyl groups to cytosine bases in DNA, typically repressing gene transcription.

Histone modification: Post-translational chemical changes to histone proteins, such as methylation or acetylation, that influence chromatin structure and gene activity.

Small non-coding RNA: Short RNA molecules in sperm that do not code for proteins but regulate gene expression and may convey environmental information to the embryo.

Macronutrient balance: Proportion of proteins, fats and carbohydrates in the diet, which can differentially affect metabolic signalling and epigenetic marks.

References

1. Paternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring. Nature Communications (2024).
2. Oxidative Stress in Mouse Sperm Impairs Embryo Development, Fetal Growth and Alters Adiposity and Glucose Regulation in Female Offspring. PLOS ONE (2014).
3. Paternal under-nutrition programs metabolic syndrome in offspring which can be reversed by antioxidant/vitamin food fortification in fathers. Scientific Reports (2016).
4. Paternal Obesity‐Induced H3K27me3 Elevation Leads to MANF‐Mediated Transgenerational Metabolic Dysfunction in Female Offspring. Advanced Science (2025).
5. Paternal high-fat diet altered SETD2 gene methylation in sperm of F0 and F1 mice. Genes & Nutrition (2023).
6. Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study. Clinical Epigenetics (2016).