Exposure to maternal diabetes is increasingly recognized as a risk factor for chronic respiratory disease in children. It is currently unclear, however, whether maternal diabetes affects the lung health of male and female offspring equally. This study characterizes the sex-specific impact of a murine model of diet-induced gestational diabetes (GDM) on offspring lung function and airway inflammation. Female adult mice are fed a high-fat (45% kcal) diet for 6-weeks prior to mating. Control offspring are from mothers fed a low fat (10% kcal) diet. Offspring were weaned and fed a chow diet until 10-weeks of age, at which point lung function was measured and lung lavage was collected. Male, but not female offspring exposed to GDM had increased lung compliance and reduced lung resistance at baseline. Female offspring exposed to GDM displayed increased methacholine reactivity and elevated levels of pro-inflammatory cytokines (e.g. interleukin (IL)-1β, IL-5, and CXCL1) in lung lavage. Female GDM offspring also displayed elevated abundance of matrix metalloproteinases (MMP) within their airways, namely MMP-3 and MMP-8. These results indicate disparate effects of maternal diabetes on lung health and airway inflammation of male and female offspring exposed to GDM. Female mice may be at greater risk of inflammatory lung conditions, such as asthma, while male offspring display changes that more closely align with models of chronic obstructive pulmonary disease. In conclusion, there are important sex-based differences in the impact of maternal diabetes on offspring lung health that could signal differences in future disease risk.
Since 2000, more than 400 000 babies worldwide have died of congenital diaphragmatic hernia (CDH), a condition that is occurring as frequently as cystic fibrosis and characterised by underdeveloped lungs ( pulmonary hypoplasia), persistent pulmonary hypertension and a diaphragmatic defect [1]. CDH can be diagnosed prenatally with ultrasound and fetal MRI, but outcome prediction and diagnostic accuracy remain imperfect [2]. The observed over expected lung-to-head (O/E LHR) ratio at 22-23 and 32-33 weeks of gestation is currently used to predict CDH outcomes [3]. A prenatal biomarker for the assessment of disease severity and prognostication has not been established yet. In contrast to cystic fibrosis, a common genetic cause has not been identified for CDH, suggesting that epigenetic and environmental factors are involved in the pathogenesis. We have previously discovered that microRNA 200b (miR-200b) is highly dysregulated in hypoplastic human CDH lungs and that miR-200b administration can serve as a prenatal therapy in an animal model for CDH [4,5].Circular RNAs (circRNAs) are powerful upstream regulators of microRNAs (miRNAs). They arise from alternative splicing events of pre-mRNA where the ends are ligated together to form a circle. Their expression is organ and development specific [6]. Due to their shape, they are highly stable in body fluids (e.g. blood) and thought to be ideal biomarkers [7]. Consequently, circRNAs are under investigation as disease specific markers in different cancers and cardiovascular disease [8,9]. We hypothesised that the circRNA profile of fetal hypoplastic CDH lungs is significantly dysregulated compared with lungs from controls and that they can serve as future prenatal biomarkers for the improved outcome prediction of CDH. Our objective for this preliminary study was to profile and compare circRNAs in human fetal control and CDH lungs at two different timepoints of fetal development (mid-and end-pregnancy) to identify a profile of circRNAs that can guide a future clinical trial to test the first ever non-invasive biomarker for prenatal prognostication of CDH.After institutional review board approval (HS15293 (H2012:134)) and written consent from the parents, we used formalin-fixed, paraffin-embedded lung tissue blocks from autopsies of severe CDH cases (n=6) without associated anomalies and age-matched controls (n=6) from a previously established biobank [10]. No standardised genetic testing was performed at our institution at the time tissues were obtained. Lung tissues were derived from deceased patients at two different gestational ages (GA) (∼20 weeks GA=mid-pregnancy, versus ∼40 weeks GA=end pregnancy). Control subjects died from a condition unrelated to lung disease (e.g. chorioamnionitis, placental abruption or placental vasculopathologies), which was confirmed by independent pathological examination. Pulmonary hypoplasia was assessed post mortem and total lung weight to head circumference ratios were used to measure the degree of lung hypoplasia. CDH patients had lung wei...
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