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Placental microRNAs relate to early childhood growth trajectories

Pediatric Research volume 94, pages 341–348 (2023)Cite this article

Abstract

Background

Poor placental function is a common cause of intrauterine growth restriction, which in turn is associated with increased risks of adverse health outcomes. Our prior work suggests that birthweight and childhood obesity-associated genetic variants functionally impact placental function and that placental microRNA are associated with birthweight. To address the influence of the placenta beyond birth, we assessed the relationship between placental microRNAs and early childhood growth.

Methods

Using the SITAR package, we generated two parameters that describe individual weight trajectories of children (0–5 years) in the New Hampshire Birth Cohort Study (NHBCS, n = 238). Using negative binomial generalized linear models, we identified placental microRNAs that relate to growth parameters (FDR < 0.1), while accounting for sex, gestational age at birth, and maternal parity.

Results

Genes targeted by the six growth trajectory-associated microRNAs are enriched (FDR < 0.05) in growth factor signaling (TGF/beta: miR-876; EGF/R: miR-155, Let-7c; FGF/R: miR-155; IGF/R: Let-7c, miR-155), calmodulin signaling (miR-216a), and NOTCH signaling (miR-629).

Conclusions

Growth-trajectory microRNAs target pathways affecting placental proliferation, differentiation and function. Our results suggest a role for microRNAs in regulating placental cellular dynamics and supports the Developmental Origins of Health and Disease hypothesis that fetal environment can have impacts beyond birth.

Impact

  • We found that growth trajectory associated placenta microRNAs target genes involved in signaling pathways central to the formation, maintenance and function of placenta; suggesting that placental cellular dynamics remain critical to infant growth to term and are under the control of microRNAs.

  • Our results contribute to the existing body of research suggesting that the placenta plays a key role in programming health in the offspring.

  • This is the first study to relate molecular patterns in placenta, specifically microRNAs, to early childhood growth trajectory.

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Fig. 1: Participation in weight observation collection.
Fig. 2: NHBCS growth curves.
Fig. 3: Differential expression analysis results.
Fig. 4: The potential roles of growth trajectory microRNAs in the cellular dynamics of placental trophoblasts.

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Data availability

RICHS total RNA-seq raw reads have been deposited at the NCBI database of Genotypes and Phenotypes (dbGaP) (phs001586). RICHS and NHBCS microRNA count matrices (https://doi.org/10.15139/S3/FUC5EW) and covariate data (https://doi.org/10.15139/S3/O9KYGB) are available at Dataverse.

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Funding

This work was supported by the National Institutes of Health (NIEHS R24ES028507, R01ES025145, P30ES019776, NIMHD R01MD011698 and NICHD K99HD104991).

Author information

Authors and Affiliations

  1. Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia

    Elizabeth M. Kennedy, Karen Hermetz, Amber Burt & Carmen J. Marsit

  2. Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, USA

    Dong Pei & Devin C. Koestler

  3. Department of Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ke Hao

  4. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jia Chen

  5. Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, Hanover, NH, USA

    Diane Gilbert-Diamond & Margaret R. Karagas

  6. Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia

    Usha Ramakrishnan

  7. Children’s Environmental Health and Disease Prevention Research Center at Dartmouth, Dartmouth College, Lebanon, Hanover, NH, USA

    Margaret R. Karagas

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Contributions

E.M.K., D.C.K., K.H., J.C., D.G.-D., M.R.K. and C.J.M. conceptualized and designed the study. K.H., A.B. and D.P. acquired data. E.M.K. analyzed and interpreted the data. E.M.K. Drafted the article. K.H., A.B., D.P., D.C.K., K.H., J.C., D.G.-D., U.R., M.R.K. and C.J.M. critically reviewed and carefully revised the article. All authors approved of the version to be published.

Corresponding author

Correspondence to Carmen J. Marsit.

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The authors declare no competing interests.

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All participants provided written, informed consent and all protocols were approved by the IRBs at the Women & Infants Hospital of Rhode Island, Dartmouth College and Emory University, respectively.

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Kennedy, E.M., Hermetz, K., Burt, A. et al. Placental microRNAs relate to early childhood growth trajectories. Pediatr Res 94, 341–348 (2023). https://doi.org/10.1038/s41390-022-02386-0

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