In a University of Bristol and University of Sheffield co-led study in mice, researchers show that both under-nutrition (low-protein intake) and a high fat/high sugar “Western” diet in fathers before conception can alter fetal growth patterns and profoundly change placental gene expression in sex-specific ways. Bristol-led, gold-standard 3D quantitative analysis (design-based stereology) found these molecular shifts occur without major changes in late-gestation placental structure.

A father’s diet and metabolic health before conception may influence pregnancy biology more than previously recognised, according to new research co-led by the University of Bristol and the University of Sheffield.

Using a controlled mouse model, the team found that sub-optimal paternal diets could affect fetal growth in late gestation and reprogramme the placenta’s gene expression profile. Notably, the placenta’s normal male-female differences in gene expression were dramatically reduced after paternal dietary challenge, suggesting a potential mechanism by which paternal health can shape developmental trajectories in a sex-specific manner.

Key findings

• Sex-specific fetal effects: paternal low-protein and some supplemented regimens increased the proportion of low-weight fetuses; female fetuses were particularly affected in specific groups.
• Early placenta changes: paternal low-protein diet was associated with altered early placental development signals (including reduced invasion depth and trends for altered alignment) at embryonic day 8.5.
• Placental gene programme: in control pregnancies the placenta showed 301 sexually dimorphic genes; across the other paternal diet groups this fell sharply (to 13, 0, 14 and 15 sex-differential genes, depending on diet), indicating a marked loss of placental sexual dimorphism.
• Robust 3D structure measurements: Bristol-led design-based stereology found no significant differences in mean late-gestation placental volume, compartment volumes, maternal blood space, or maternal blood and fetal capillary surface areas between paternal diet groups.
• Paternal health signals despite preserved fertility: Western-diet fathers showed increased adiposity, altered liver lipids and gut microbiota, and testicular tubule anomalies and gene-expression changes, even though fundamental fertility measures were not impaired.

Why this matters for human health

Diet-related non-communicable diseases such as obesity, metabolic-associated fatty liver disease and type 2 diabetes are rising globally. This study supports the idea that men’s preconception health may contribute to pregnancy and offspring outcomes, potentially via molecular reprogramming of the placenta that differs between male and female fetuses. Although conducted in mice, the placenta’s core roles are conserved across mammals, and the findings strengthen the case for including fathers more explicitly in preconception health guidance and research.

University of Bristol contribution

The University of Bristol, led by Dr Augusto Coppi, directed the study’s 3D quantitative analysis of placental structure using design-based stereology. This gold-standard method combines systematic random sampling with unbiased estimators to deliver robust measurements of placental volumes and exchange-related surface areas, strengthening conclusions about how placental structure supports function. Dr Coppi is an internationally recognised expert in stereology.

Publication

Morgan HL, Eid N, Holmes N, et al. (2026) Paternal over- and under-nutrition program fetal and placental development in a sex-specific manner in mice. eLife, 15:RP109392.

• https://elifesciences.org/reviewed-preprints/109392

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