Intrauterine smoke exposure deregulates lung function, pulmonary transcriptomes, and in particular insulin-like growth factor (IGF)-1 in a sex-specific manner

Stefan Dehmel,Machteld Hylkema,Johannes Beckers,Ali Oender Yildirim,Natalia El-Merhie,Sabine Bartel,Petra Nathan,Oliver Eickelberg,Susanne Krauss-Etschmann,Gerrit John-Schuster,Hagen Scherb,Katrin Milger,Martin Irmler,Bianca Schaub

doi:10.1038/s41598-018-25762-5

Abstract

Prenatal exposure to tobacco smoke is a significant risk-factor for airway disease development. Furthermore, the high prevalence of pregnant smoking women requires the establishment of strategies for offspring lung protection. Therefore, we here aimed to understand the molecular mechanism of how prenatal smoke exposure affects fetal lung development. We used a mouse model recapitulating clinical findings of prenatally exposed children, where pregnant mice were exposed to smoke until c-section or spontaneous delivery, and offspring weight development and lung function was monitored. Additionally, we investigated pulmonary transcriptome changes in fetal lungs (GD18.5) by mRNA/miRNA arrays, network analyses and qPCR. The results demonstrated that prenatally exposed mice showed intrauterine and postnatal growth retardation, and impaired lung function. 1340 genes and 133 miRNAs were found to be significantly dysregulated by in utero smoke exposure, and we identified Insulin-like growth factor 1 (Igf1) as a top hierarchical node in a network analysis. Moreover, Igf1 mRNA was increased in female murine offspring and in prenatally exposed children. These findings suggest that prenatal smoking is associated with a dysregulation of several genes, including Igf1 in a sex-specific manner. Thus, our results could represent a novel link between smoke exposure, abberant lung development and impaired lung function.

Highlights

Prenatal exposure to tobacco smoke is a significant risk-factor for airway disease development
One of these factors is insulin-like growth factor (IGF), while it was shown that mice depleted from either Igf[1] or its receptor Igf1r demonstrated a failure in lung development[27,28]
Since the in silico analyses suggested Igf[1] as a main driver of reduced lung weight and function, we further focused on this growth hormone

Summary

Introduction

Prenatal exposure to tobacco smoke is a significant risk-factor for airway disease development. Even a sole exposure to maternal nicotine, a component of tobacco smoke, affects the metabolism and the structuaral development of the offspring lung[6]. Risk of preschool wheeze[7,8,9], asthma[8,9] and COPD10–12 in the offspring Despite this knowledge and intensive anti-tobacco campaigns in several countries, the number of women smoking during pregnancy remains high worldwide. It was shown that grandmaternal smoking affects asthma susceptibility[16,17,18] in grandchildren These observations were supported by studies in rats where maternal perinatal s.c. nicotine induced airway hyperreactivity until the 3rd generation[19]. It is important to develop means to protect the developing fetal lung as well as to understand the mechanisms of how cigarette smoke affects fetal and early postnatal lung development

Objectives

Methods

Results

Conclusion