Gene expression profile of androgen modulated genes in the murine fetal developing lung

Eva Bresson,Pierre R Provost,Yves Tremblay,Bruno Piedboeuf,Tommy Seaborn,Geneviève Cormier,Mélissa Côté

doi:10.1186/1477-7827-8-2

Eva Bresson, Pierre R Provost + Show 5 more

Open Access

https://doi.org/10.1186/1477-7827-8-2

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Abstract

BackgroundAccumulating evidences suggest that sex affects lung development. Indeed, a higher incidence of respiratory distress syndrome is observed in male compared to female preterm neonates at comparable developmental stage and experimental studies demonstrated an androgen-related delay in male lung maturation. However, the precise mechanisms underlying these deleterious effects of androgens in lung maturation are only partially understood.MethodsTo build up a better understanding of the effect of androgens on lung development, we analyzed by microarrays the expression of genes showing a sexual difference and those modulated by androgens. Lungs of murine fetuses resulting from a timely mating window of 1 hour were studied at gestational day 17 (GD17) and GD18, corresponding to the period of surge of surfactant production. Using injections of the antiandrogen flutamide to pregnant mice, we hunted for genes in fetal lungs which are transcriptionally modulated by androgens.ResultsResults revealed that 1844 genes were expressed with a sexual difference at GD17 and 833 at GD18. Many genes were significantly modulated by flutamide: 1597 at GD17 and 1775 at GD18. Datasets were analyzed by using in silico tools for reconstruction of cellular pathways. Between GD17 and GD18, male lungs showed an intensive transcriptional activity of proliferative pathways along with the onset of lung differentiation. Among the genes showing a sex difference or an antiandrogen modulation of their expression, we specifically identified androgen receptor interacting genes, surfactant related genes in particularly those involved in the pathway leading to phospholipid synthesis, and several genes of lung development regulator pathways. Among these latter, some genes related to Shh, FGF, TGF-beta, BMP, and Wnt signaling are modulated by sex and/or antiandrogen treatment.ConclusionOur results show clearly that there is a real delay in lung maturation between male and female in this period, the latter pursuing already lung maturation while the proper is not yet fully engaged in the differentiation processes at GD17. In addition, this study provides a list of genes which are under the control of androgens within the lung at the moment of surge of surfactant production in murine fetal lung.

Highlights

Accumulating evidences suggest that sex affects lung development
In order to assess the validity of the microarrays, we achieved real-time quantitative PCR for a few genes randomly selected among those presenting sexual difference and/or flutamide sensitivity by using cDNA from the same experimental groups than those used for microarray experiments
The genes considered for quantitative PCR were cyclin-dependant kinase 6 (Cdk6), nuclear factor I/B (Nfib), pre B-cell leukemia transcription factor 1 (Pbx1), phosphatase and tensin homolog (Pten), sirtuin 1 (Sirt1), and nuclear receptor subfamily 2, group C, member 2 (Nr2c2)

Summary

Introduction

Accumulating evidences suggest that sex affects lung development. A higher incidence of respiratory distress syndrome is observed in male compared to female preterm neonates at comparable developmental stage and experimental studies demonstrated an androgen-related delay in male lung maturation. The precise mechanisms underlying these deleterious effects of androgens in lung maturation are only partially understood. Accumulating evidence suggests that sex affects lung development and physiology. Sex hormones appear to exert regulatory effects on human lung development and maturation during both fetal and neonatal periods. Male lung maturation is delayed compared with female and surfactant pathology of the neonate for which RDS is not always an anterior event [5]. Androgens have been shown to exert inhibitory effects on lung maturation both in vitro [7] and in vivo [8,9]. Androgens delay fetal lung surfactant production in a variety of species [11] by a mechanism involving transforming growth factor-b (TGF-b) signalling pathway [12]

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