Intrauterine Smoke Exposure, microRNA Expression during Human Lung Development, and Childhood Asthma

Abstract

Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development. We hypothesized that miRNA–mRNA networks are dysregulated by IUS during human lung development and that these miRNAs may be associated with future risk of asthma and allergy. Human fetal lung samples from a prenatal tissue retrieval program were tested for differential miRNA expression with IUS exposure (measured using placental cotinine concentration). RNA was extracted and miRNA-sequencing was performed. We performed differential expression using IUS exposure, with covariate adjustment. We also considered the above model with an additional sex-by-IUS interaction term, allowing IUS effects to differ by male and female samples. Using paired gene expression profiles, we created sex-stratified miRNA–mRNA correlation networks predictive of IUS using DIABLO. We additionally evaluated whether miRNAs were associated with asthma and allergy outcomes in a cohort of childhood asthma. We profiled pseudoglandular lung miRNA in n = 298 samples, 139 (47%) of which had evidence of IUS exposure. Of 515 miRNAs, 25 were significantly associated with intrauterine smoke exposure (q-value < 0.10). The IUS associated miRNAs were correlated with well-known asthma genes (e.g., ORM1-Like Protein 3, ORDML3) and enriched in disease-relevant pathways (oxidative stress). Eleven IUS-miRNAs were also correlated with clinical measures (e.g., Immunoglobulin E andlungfunction) in children with asthma, further supporting their likely disease relevance. Lastly, we found substantial differences in IUS effects by sex, finding 95 significant IUS-miRNAs in male samples, but only four miRNAs in female samples. The miRNA–mRNA correlation networks were predictive of IUS (AUC = 0.78 in males and 0.86 in females) and suggested that IUS-miRNAs are involved in regulation of disease-relevant genes (e.g., A disintegrin and metalloproteinase domain 19 (ADAM19), LBH regulator of WNT signaling (LBH)) and sex hormone signaling (Coactivator associated methyltransferase 1(CARM1)). Our study demonstrated differential expression of miRNAs by IUS during early prenatal human lung development, which may be modified by sex. Based on their gene targets and correlation to clinical asthma and atopy outcomes, these IUS-miRNAs may be relevant for subsequent allergy and asthma risk. Our study provides insight into the impact of IUS in human fetal lung transcriptional networks and on the developmental origins of asthma and allergic disorders.

Identification and Analysis of Sex-Biased MicroRNAs in Human Diseases

“…For example, a recent study by Deny et al found that miRNA expression profiles differed between males and females during cystic fibrosis [ 6 ], while Gunay et al found significant miRNA differences between mice of different sexes in the methanol intoxication state [ 7 ]. Kahnamoui et al found that respiratory sensitivity was associated with miRNA expression levels in mice of different sexes [ 8 ]; Rosenberg et al found an association between the effects of different sexes on smoking and lung development [ 9 ]. In addition, research showed that certain miRNAs are expressed differently in different sexes during fetal development [ 10 , 11 ], which, in turn, results in different developmental processes.…”

Editorial of Special Issue “Molecular Mechanisms of Allergy and Asthma 2.0”

“…Wieczfinska and Pawliczak [15] in turn investigated signaling pathways and transcription regulation involved in airway remodeling in connection with rhinoviral infection. In addition, Rosenberg and coworkers [16] analyzed the effects of prenatal smoke exposure on microRNA expression in fetal lung and their effects on susceptibility to later development of asthma and allergies, while Kaczy ńska et colleagues [17] comprehensively summarized current knowledge on the role of regulatory peptides in asthma.…”