# Epigenetic mediation may explain intergenerational associations between maternal obesogenic lifestyle and children’s birth weight: findings from the NorthPop prospective birth cohort

## TL;DR

This study explores how a mother's lifestyle during pregnancy affects her child's birth weight, possibly through epigenetic changes.

## Contribution

The study identifies specific DNA methylation sites that may mediate the effects of maternal BMI and weight gain on offspring birth weight.

## Key findings

- Maternal BMI and gestational weight gain are significantly associated with offspring birth weight.
- Multiple DNA methylation sites are identified as potential mediators of these associations.
- Both single and multiple mediation pathways are found to be involved in the observed effects.

## Abstract

Epigenetic alterations during fetal development have been proposed as key factors explaining associations between maternal lifestyle during pregnancy and later health outcomes in the offspring, pertaining to the developmental origin of health and disease hypothesis.

To assess the association of maternal lifestyle with offsprings’ birth weight and underlying epigenetic mediatory mechanisms in the NorthPop prospective birth cohort.

A three-step analytic pipeline was applied. In 722 mother–child pairs, overall associations between ten maternal lifestyle factors and the offspring’s standardized birth weight were first evaluated by multiple linear regression. Three high-dimensional mediation methods, based on sure independence screening and penalized regression, were then applied on the beta methylation matrix to identify candidate CpG mediators in cord blood driving the significant overall associations. Finally, robust and ordinary least squares (OLS) regression-based classical mediation methods were used with candidate CpG probes to assess single- and multiple (parallel and serial)-mediator models on a low-dimensional space.

Gestational weight gain (GWG) (β-adj = 0.03; p = 2 × 10–5) and maternal BMI at the beginning of pregnancy (β-adj = 0.036; p = 1 × 10–4) were significantly associated with the offspring’s standardized birth weight. High-dimensional mediation analyses identified pooled sets of four (cg19242268 [TCEA2]; cg08461903 [N/A]; cg14798382 [CHERP/C19orf44] and cg21516291 [SLC35C2]) and five (cg17040807 [CYGB]; cg19242268 [TCEA2]; cg26552621 [CIRBP]; cg04457572 [CDH23] and cg06457011 [PLCG1]) candidate CpG mediators related to GWG and BMI at the beginning of pregnancy, respectively. For both exposures, classical mediation analyses revealed a range of significant single- and multiple (both serial and parallel)-mediator models via both robust and OLS regression based approaches. These indicated the likely presence of individual, causally linked multiple, and causally independent multiple mediatory pathways underlying the two significant overall associations.

Our findings support the hypothesis that neonatal health effects related to maternal lifestyle may be partly mediated by epigenetic alterations. Findings also suggest the possible involvement of multiple DNA methylation sites via various mediatory pathways.

The online version contains supplementary material available at 10.1186/s13148-025-02001-z.