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Adverse early-life environment impairs postnatal lung development in mice. Physiol Genomics 2019 09 01;51(9):462-470

Date

08/03/2019

Pubmed ID

31373541

Pubmed Central ID

PMC6766700

DOI

10.1152/physiolgenomics.00016.2019

Scopus ID

2-s2.0-85072265843   3 Citations

Abstract

BACKGROUND: Fetal growth restriction (FGR) is a major risk factor for bronchopulmonary dysplasia (BPD). Maternal stress and poor diet are linked to FGR. Effect of perinatal stress on lung development remains unknown.

OBJECTIVE: Using a murine model of adverse early life environment (AELE), we hypothesized that maternal exposure to perinatal environmental stress and high-fat diet (Western diet) lead to impaired lung development in the offspring.

METHODS: Female mice were placed on either control diet or Western diet before conception. Those exposed to Western diet were also exposed to perinatal environmental stress, the combination referred to as AELE. Pups were either euthanized at postnatal day 21 (P21) or weaned to control diet and environment until adulthood (8-14 wk old). Lungs were harvested for histology, gene expression by quantitative RT-PCR, microRNA profiling, and immunoblotting.

RESULTS: AELE increased the mean linear intercept and decreased the radial alveolar count and secondary septation in P21 and adult mice. Capillary count was also decreased in P21 and adult mice. AELE lungs had decreased vascular endothelial growth factor A (VEGFA), VEGF receptor 2, endothelial nitric oxide synthase, and hypoxia inducible factor-1α protein levels and increased expression of genes that regulate DNA methylation and upregulation of microRNAs that target genes involved in lung development at P21.

CONCLUSION: AELE leads to impaired lung alveolar and vascular growth, which persists into adult age despite normalizing the diet and environment at P21. AELE also alters the expression of genes involved in lung remodeling.

Author List

Lai PY, Jing X, Michalkiewicz T, Entringer B, Ke X, Majnik A, Kriegel AJ, Liu P, Lane RH, Konduri GG

Authors

Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Alison J. Kriegel PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
DNA Methylation
Diet, Western
Disease Models, Animal
Female
Fetal Growth Retardation
Hypoxia-Inducible Factor 1, alpha Subunit
Lung
Male
Mice
Mice, Inbred C57BL
MicroRNAs
Nitric Oxide Synthase
Organogenesis
Pregnancy
Stress, Physiological
Transcriptome
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2