Strength of evidence for paternal influence on offspring epigenome in observational human studies: a systematic review and risk-of-bias appraisals for non-randomized exposures

Abstract

Paternal influence on the offspring epigenome is difficult to interpret in observational human studies due to heterogeneous designs, causing varying susceptibility to bias and non-causal explanations. We conducted a systematic review (CRD42022302695) of paternal exposures before or during pregnancy in relation to the offspring epigenome, focusing on characteristics affecting causal interpretation and reproducibility. We searched three electronic databases for human studies published between 2003 and 2023. Eligible studies assessed paternal factors before or during pregnancy as exposures, and epigenetic mechanisms as outcomes. Risk of bias (RoB) was evaluated using ROBINS-E. The most frequently studied paternal factors were BMI/obesity (7), age (7), smoking (5), and socioeconomic status (SES) (4). All 28 studies assessed DNA methylation; two additionally explored miRNA expression. Most studies were rated ‘high’ or ‘very high’ RoB, primarily due to unclear exposure measurement and confounding. Findings showed limited overlap in CpG sites and genomic regions across studies. However, exposures that were stable (e.g. SES) or had clearly defined timing produced more consistent results. Notably, studies with clearly defined timing of paternal smoking suggested preconception exposure may influence offspring epigenetic pathways related to innate immunity but not pregnancy exposure. In contrast, paternal factors with poorly defined experimental analogues, such as BMI, provided inconsistent results. Aligning study design more closely with clinical trials or animal models, by clearly defining populations and exposures, may result in more reliable and replicable findings. Frameworks like ‘target trial emulation,’ offer a promising approach to improve reproducibility and interpretability of future research on paternal effects on offspring epigenome.

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Identifiers

ORCID for Mark A. Burton: orcid.org/0000-0002-7117-8151

ORCID for Keith M. Godfrey: orcid.org/0000-0002-4643-0618

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