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Fetal programming and lactation: modulating gene expression in response to undernutrition during intrauterine life

Pediatric Research (2024)Cite this article

Abstract

Background

Adverse environmental conditions during intrauterine life, known as fetal programming, significantly contribute to the development of diseases in adulthood. Fetal programming induced by factors like maternal undernutrition leads to low birth weight and increases the risk of cardiometabolic diseases.

Methods

We studied a rat model of maternal undernutrition during gestation (MUN) to investigate gene expression changes in cardiac tissue using RNA-sequencing of day 0–1 litters. Moreover, we analyzed the impact of lactation at day 21, in MUN model and cross-fostering experiments, on cardiac structure and function assessed by transthoracic echocardiography, and gene expression changes though qPCR.

Results

Our analysis identified specific genes with altered expression in MUN rats at birth. Two of them, Agt and Pparg, stand out for being associated with cardiac hypertrophy and fibrosis. At the end of the lactation period, MUN males showed increased expression of Agt and decreased expression of Pparg, correlating with cardiac hypertrophy. Cross-fostering experiments revealed that lactation with control breastmilk mitigated these expression changes reducing cardiac hypertrophy in MUN males.

Conclusions

Our findings highlight the interplay between fetal programming, gene expression, and cardiac hypertrophy suggesting that lactation period is a potential intervention window to mitigate the effects of fetal programming.

Impact

  • Heart remodeling involves the alteration of several groups of genes and lactation period plays a key role in establishing gene expression modification caused by fetal programming.

  • We could identify expression changes of relevant genes in cardiac tissue induced by undernutrition during fetal life.

  • We expose the contribution of the lactation period in modulating the expression of Agt and Pparg, relevant genes associated with cardiac hypertrophy.

  • This evidence reveal lactation as a crucial intervention window for preventing or countering fetal programming.

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Fig. 1: Body and heart weighs at birth in MUN male and female rats.
Fig. 2: Differential gene expression at birth in MUN male rats.
Fig. 3: Differential Agt and Pparg expression in MUN and cross-fostered rats.
Fig. 4: Left ventricular mass index (LVMI) and ejection fraction (EF) in MUN and cross-fostered rats.
Fig. 5: Graphical abstract summarizing cardiac gene expression modulation in response to undernutrition and the impact of lactation period.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This research was funded by Ministerio de Ciencia, Innovación y Universidades from Spain (grant number RTI2018-097504-B-I00), Instituto de Salud Carlos III (ISCIII) (grant number PI20/00306) with co-funding from the European Regional Development Fund (ERDF) “A way to build Europe”. R.G.B. was supported by the UAM and the MCNU FPU program (FPU19/01774) and A.S. by Universidad Francisco de Vitoria.

Author information

Author notes

  1. These authors contributed equally: Ignacio Monedero Cobeta, Raquel Gomez Bris.

Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, 28029, Madrid, Spain

    Ignacio Monedero Cobeta, Raquel Gomez Bris, Pilar Rodríguez-Rodríguez & Silvia Magdalena Arribas

  2. LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041, Madrid, Spain

    Raquel Gomez Bris, Angela Saez & Jose Maria González Granado

  3. Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223, Pozuelo de Alarcón, Spain

    Angela Saez

  4. Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain

    Begoña Quintana-Villamandos

  5. Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain

    Jose Maria González Granado

  6. CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029, Madrid, Spain

    Jose Maria González Granado

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  1. Ignacio Monedero Cobeta
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Contributions

I.M.C., R.G.B., P.R.-R., A.S., S.M.A.: data acquisition and data analysis (animal model, tissue dissection). P.R.-R., B.Q.-V.: data acquisition, analysis, and interpretation (echocardiography). I.M.C., R.G.B., J.M.G.G., S.M.A.: data acquisition, analysis, and interpretation (RNAseq analysis). I.M.C., R.G.B, J.M.G.G., S.M.A.: data acquisition, analysis, and interpretation (qPCR analysis). I.M.C., J.M.G.G., S.M.A.: conception or design of the work, drafting of the manuscript and project administration. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Jose Maria González Granado or Silvia Magdalena Arribas.

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Competing interests

The authors declare no competing interests.

Ethics approval

The study was conducted according to the guidelines of the Declaration of Helsinki, and it was approved by the Ethics Review Boards of Universidad Autónoma de Madrid (CEI-UAM 96-1776-A286) and the Regional Environment Committee of the Comunidad Autónoma de Madrid (RD 53/2013; Ref. PROEX 04/19; date 19 March 2019).

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Monedero Cobeta, I., Gomez Bris, R., Rodríguez-Rodríguez, P. et al. Fetal programming and lactation: modulating gene expression in response to undernutrition during intrauterine life. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03042-5

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