Sex-Specific Differences in MicroRNA Expression During Human Fetal Lung Development

Abstract

Background: Sex-specific differences in fetal lung maturation have been well described; however, little is known about the sex-specific differences in microRNA (miRNA) expression during human fetal lung development. Interestingly, many adult chronic lung diseases also demonstrate sex-specific differences in prevalence. The developmental origins of health and disease hypothesis suggests that these sex-specific differences in fetal lung development may influence disease susceptibility later in life. In this study, we performed miRNA sequencing on human fetal lung tissue samples to investigate differential expression of miRNAs between males and females in the pseudoglandular stage of lung development. We hypothesized that differences in miRNA expression are present between sexes in early human lung development and may contribute to the sex-specific differences seen in pulmonary diseases later in life.Methods: RNA was isolated from human fetal lung tissue samples for miRNA sequencing. The count of each miRNA was modeled by sex using negative binomial regression models in DESeq2, adjusting for post-conception age, age2, smoke exposure, batch, and RUV factors. We tested for differential expression of miRNAs by sex, and for the presence of sex-by-age interactions to determine if miRNA expression levels by age were distinct between males and females.Results: miRNA expression profiles were generated on 298 samples (166 males and 132 females). Of the 809 miRNAs expressed in human fetal lung tissue during the pseudoglandular stage of lung development, we identified 93 autosomal miRNAs that were significantly differentially expressed by sex and 129 miRNAs with a sex-specific pattern of miRNA expression across the course of the pseudoglandular period.Conclusion: Our study demonstrates differential expression of numerous autosomal miRNAs between the male and female developing human lung. Additionally, the expression of some miRNAs are modified by age across the pseudoglandular stage in a sex-specific way. Some of these differences in miRNA expression may impact susceptibility to pulmonary disease later in life. Our results suggest that sex-specific miRNA expression during human lung development may be a potential mechanism to explain sex-specific differences in lung development and may impact subsequent disease susceptibility.

The impact of gender medicine on neonatology: the disadvantage of being male: a narrative review

“…Another hypothesis focuses on the alveolar epithelial transport of Na + as a determinant of the perinatal pulmonary transition [ 27 ], with differences among the sexes. Finally, a study carried out by measuring the diversity in the expression of microRNA during fetal lung development hypothesized its role as a cofactor in lung diseases, both in neonatal and adulthood [ 28 ].…”

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“…and signaling cascades (the EGF‐AKT signaling axis, the ERK‐MMP9 cascade and the Hippo signaling pathway, etc. ), that is essential for the development of OSCC (Lin, Han, et al, 2022; Lin, Liu, et al, 2022; Lin, Wu, et al, 2022). They find their way into the oral cavity from multiple sources, such as salivary glands, gingival crevicular fluid, and shed oral epithelial cells (Zahran et al, 2015).…”

“…Numerous factors influence miRNA expression levels, including age (Eshkoor et al, 2022; Jin Jung & Suh, 2012), gender (Lin, Han, et al, 2022; Lin, Liu, et al, 2022; Lin, Wu, et al, 2022), lifestyle (Panico et al, 2021), and an individual's disease history (Li & Kowdley, 2012). Multiple factors collaboratively influence the expression level of miRNA.…”

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma

“…Notably, over 100 miRNAs are encoded on 6 the X chromosome, while only 2 miRNAs are encoded on the Y chromosome 19 , which has led to studies of the association between miRNAs and sex differences. Additionally, both male and female sex hormones are known to influence miRNA expression 20,21. Sex differences in miRNA expression have been reported in multiple tissues, including lung and brain 22,23 . Various diseases including lupus and metabolic syndrome also display a sex bias in miRNA expression 24,25 .…”

“…Additionally, both male and female sex hormones are known to influence miRNA expression 20,21 . Sex differences in miRNA expression have been reported in multiple tissues, including lung and brain 22,23 . Various diseases including lupus and metabolic syndrome also display a sex bias in miRNA expression 24,25 .…”