Introduction: The human fetal adrenal has unique structure/function and produces hormones (DHEA, corticoids, catecholamines) that control fetal development, organ maturation and parturition. Maternal smoking during pregnancy has immediate (pre-term delivery, low birth weight) and long-term effects on the offspring (metabolic syndrome, disrupted adrenal function). We performed shotgun proteomics to characterise human fetal adrenal development and to explore adverse effects of maternal smoking.
Methods: Proteins from human fetal adrenals (1219 weeks of gestation, divided by sex and maternal smoke exposure, n=15/group) from electively terminated fetuses (REC 04/S0802/21) were digested and the peptides analysed by liquid chromatography/Q-Exactive tandem Mass Spectrometry. Identified proteins were normalised using MaxQuant software and compared across groups and gestational ages using empirical moderated Bayesian statistics (limma package, R statistical software). Statistically-significant differences were filtered on a 10% False Discovery Rate and mapped using Ingenuity Pathway Analysis software.
Results and Discussion: Of 2488 human fetal adrenal proteins quantified, 423 were developmentally regulated; 39 had sex-specific expression and; 71 in females and 51 in male adrenals were dysregulated by maternal smoking. Development of the adrenal associated with reduced protein translation, increased proliferation, tissue remodelling and hypoxia signalling, as well as elevated T3 hormone, leptin and retinoid signalling. Higher levels of cholesterol and glucocorticoid biosynthesis enzymes and increased androgen receptor signalling characterised male adrenals. Maternal smoking: (i) increased cholesterol transport and proliferative pathways in females, suggesting accelerated adrenal development likely to contribute to preterm birth; (ii) increased proapoptotic factors and disrupted glucocorticoid receptor, xenobiotic metabolism, and calcium homeostasis pathways in males, suggesting alterations in the HPA axis consistent with low birth weight outcomes. Our results show that human fetal adrenals have sexually-dimorphic responses to maternal smoking and suggest that the links between in utero smoke exposure and disease involve fetal adrenal disruption. Funded by an SfE Early Career Grant (2015).
07 Nov 2016 - 09 Nov 2016