Dataset Information

Adverse early-life environment impairs postnatal lung development in mice.

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-1? 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.

SUBMITTER: Lai PY

PROVIDER: S-EPMC6766700 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Adverse early-life environment impairs postnatal lung development in mice.

Lai Pui Y PY Jing Xigang X Michalkiewicz Teresa T Entringer Brianna B Ke Xingrao X Majnik Amber A Kriegel Alison J AJ Liu Pengyuan P Lane Robert H RH Konduri Girija G GG

Physiological genomics 20190802 9

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Methods</h4>Female mice were placed ...[more]

PMID: 31373541

Similar Datasets

Project description:BackgroundBronchopulmonary dysplasia continues to cause important respiratory morbidity throughout life, and new therapies are needed. The common denominator of all BPD cases is preterm birth, however most preclinical research in this area focusses on the effect of hyperoxia or mechanical ventilation. In this study we investigated if and how prematurity affects lung structure and function in neonatal rabbits.MethodsPups were delivered on either day 28 or day 31. For each gestational age a group of pups was harvested immediately after birth for lung morphometry and surfactant protein B and C quantification. All other pups were hand raised and harvested on day 4 for the term pups and day 7 for the preterm pups (same corrected age) for lung morphometry, lung function testing and qPCR. A subset of pups underwent microCT and dark field imaging on day 0, 2 and 4 for terms and on day 0, 3, 5 and 7 for preterms.ResultsPreterm pups assessed at birth depicted a more rudimentary lung structure (larger alveoli and thicker septations) and a lower expression of surfactant proteins in comparison to term pups. MicroCT and dark field imaging revealed delayed lung aeration in preterm pups, in comparison to term pups. Preterm birth led to smaller pups, with smaller lungs with a lower alveolar surface area on day 7/day 4. Furthermore, preterm birth affected lung function with increased tissue damping, tissue elastance and resistance and decreased dynamic compliance. Expression of vascular endothelial growth factor (VEGFA) was significantly decreased in preterm pups, however in the absence of structural vascular differences.ConclusionsPreterm birth affects lung structure and function at birth, but also has persistent effects on the developing lung. This supports the use of a preterm animal model, such as the preterm rabbit, for preclinical research on BPD. Future research that focuses on the identification of pathways that are involved in in-utero lung development and disrupted by pre-term birth, could lead to novel therapeutic strategies for BPD.

Project description:BackgroundChromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown.MethodsWe generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months).ResultsChd8V986*/+ mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8V986*/+ mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8V986*/+ crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8V986*/+ mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8V986*/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression.LimitationsIt is unclear whether the transcriptional changes observed with age in Chd8V986*/+ mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities.ConclusionsCollectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8V986*/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8V986*/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice.

Project description:BackgroundThe impact of anesthesia and surgery on neurocognitive and behavioral development in infants and children remains inadequately understood.ObjectiveTo investigate the impact of early-life exposure to general anesthesia and surgery on cognitive and behavioral development.Methods and materialsChildren aged 0-3 years who underwent general anesthesia and surgical procedures between 2012 and 2015 were included. The cognitive and behavioral development of these children at ages 4-6 years was assessed. Age-, race-, and gender-matched children from the same geographic region, who did not undergo general anesthesia or surgery, served as the control group. The Wechsler Preschool Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) was used to evaluate children's total intelligence quotient (FSIQ) and specific cognitive domains. The Gesell Development Schedules (GSCH) and Child Behavior Checklist (CBCL) were employed to assess behavioral and personality development. Additionally, the study analyzed the effects of various factors including anesthesia drugs, surgery duration, number of surgeries, age, weight, ethnicity, and gender on postoperative neurocognitive and behavioral outcomes.ResultsThe study included 447 children with anesthesia/surgical exposure (AS) and 459 children in the control group. Analysis of cognitive and behavioral development showed a significant difference in the working memory index (WMI) between the AS and control groups (p < 0.05). Exploratory findings indicated that children administered remifentanil exhibited lower developmental quotient (DQ) values, whereas those given fentanyl showed higher (worse) Child Behavior Checklist (CBCL) total scores. Moreover, increased anesthesia/surgical exposures, younger age and lower body weight at exposure, and longer surgery durations were associated with cognitive and behavioral developmental challenges.ConclusionThis study examined the impact of early-life exposure to surgery and anesthesia on postoperative cognitive and behavioral development. Findings indicate that higher frequency of exposure to surgery and anesthesia, younger age, and lower body weight at exposure could negatively influence cognitive and behavioral development. Furthermore, variations in the effects of different anesthetics on behavior and cognition were observed. Caution is advised regarding the use of opioid analgesics such as remifentanil and fentanyl for more rigorous clinical applications.

Dataset Information

Adverse early-life environment impairs postnatal lung development in mice.

Publications

Adverse early-life environment impairs postnatal lung development in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets