Paternal low protein diet and the supplementation of methyl-donors impact fetal growth and placental development in mice

Hannah L Morgan,Arwa Aljumah,Charlène Rouillon,Adam J Watkins

doi:10.1016/j.placenta.2020.10.020

Abstract

IntroductionPaternal low-protein diet can alter sperm methylation status, fetal growth and program offspring ill-health, however its impact on the placenta remains poorly defined. Here we examine the influence paternal low-protein diet has on fetal and placental development and the additional impact of supplementary methyl-donors on fetoplacental physiology. MethodsMale C57BL/6J mice were fed a control normal protein diet (NPD; 18% protein), a low-protein diet (LPD; 9% protein) or LPD with methyl-donor supplementation (MD-LPD; choline chloride, betaine, methionine, folic acid, vitamin B12) for a minimum of 8 weeks. Males were mated with 8–11 week old female C57BL/6J mice and fetal and placental tissue collected on embryonic day 17.5. ResultsPaternal LPD was associated with increased fetal weights compared to NPD and MD-LPD with 22% fetuses being above the 90th centile for fetal weight. However, LPD and MD-LPD placental weights were reduced when compared to NPD. Placentas from LPD fathers demonstrated a reduced junctional zone area and reduced free-fatty acid content. MD-LPD placentas did not mirror these finding, demonstrating an increased chorion area, a reduction in junctional-specific glycogen staining and reduced placental Dnmt3bexpression, none of which were apparent in either NPD or LPD placentas. DiscussionA sub-optimal paternal diet can influence fetal growth and placental development, and dietary methyl-donor supplementation alters placental morphology and gene expression differentially to that observed with LPD alone. Understanding how paternal diet and micro-nutrient supplementation influence placental development is crucial for determining connections between paternal well-being and future offspring health.

Highlights

Paternal low-protein diet can alter sperm methylation status, fetal growth and program offspring illhealth, its impact on the placenta remains poorly defined
Fetuses sired from low-protein diet (LPD) fed fathers had a significantly increased weight at E17.5 compared to normal protein diet (NPD) (p = 0.0113) and mg/kg diet vitamin B12 to LPD (MD-LPD) (p = 0.0018) fe tuses. (Fig. 2A)
Fetal weight distributions revealed LPD fathers pro duced a higher proportion of ‘overgrown’ fetuses; 22% fall above the 90th centile for NPD fetal weights, this did not reach signifi cance when compared to NPD (Fig. 2B)

Summary

Introduction

Paternal low-protein diet can alter sperm methylation status, fetal growth and program offspring illhealth, its impact on the placenta remains poorly defined. Placental dysfunction can cause extremes in fetal growth, such as the development of small for gestational age (SGA) babies (defined as a fetal weight under the 10th percentile for the population at that gestational age) or fetal overgrowth (a fetal weight over the 90th percentile, termed large for gestational age (LGA)) [1,2] These abnormalities in fetal growth are highly prevalent worldwide, and have been linked to an increased risk of stillbirth and childhood morbidities [3,4,5]. David Barker and colleagues’ extensive studies of epidemiological data developed the ‘fetal programming’ hypothesis, and first demonstrated associations between maternal nutrition, impaired fetal growth and the risk of developing cardiovascular or metabolic disorders in later life [7,8,9] This hypothesis suggests exposure to sub-optimal environments during crucial developmental time-points can alter fetal growth trajectories, predisposing the offspring to increased risk of poor health in later life [6]. As our understanding of the sensitivity of the pre- and peri-conception period expands, a new focus on the role the father’s diet has for embryo development, implantation and fetal growth is emerging

Objectives

Methods

Results

Conclusion