As one of the major obstetrical diseases, the prevalence of GDM is gradually increasing worldwide, in turn leading increased mortality and morbidity rates among mothers and their offspring. Recently, more and more reports show that the occurrence of GDM is not only due to metabolic disorders during pregnancy but also related to the chronic systemic inflammatory response mediated by proinflammatory cytokines [8]. Further and foremost, increasing research evidence shows that the immune system, through immune cells and their products such as cytokines and antibodies, exerts a vital part in modulating GDM [9–10]. Studies have ascertained that in the placental villi of GDM, the increase in IL-8 and decrease in IL-10 expression are associated with fetal loss, preterm delivery, and preeclampsia. However, no association was found between the gene expression and prevalence of gestational diabetes [11–12], and its effect on metabolism in late progeny remains unclear. Therefore, it was deemed essential to study the metabolic effects and mechanisms of gestational diabetes on offspring of different sexes.
In this study, the enrichment analysis revealed 10 differential genes related to GDM, including OAS1, OAS2, OAS3, RSAD2, MX1, IFITT1, IFIT2, IFITT3, XAF1, and ISG15. The results showed that the heterogeneity of OAS1 and IFIT1 was the most significant. Thus, based on the pathway and function enrichment analysis, the DEGs may play significant roles in receptor ligand activity, signaling receptor activator activity, and extracellular organization. Extracellular tissue mainly consists of the structure organization, matrix tissue, and structure tissue containing collagen.
The IFN system performs anti-virus, immunity regulation, anti-tumor, and cell proliferation inhibitory functions. The OASs are a family of IFN- and virus-induced proteins that consist of four genes: OAS1, OAS2, OAS3, and OASL [6]. Mainly activated by the secondary structure of double- or single-stranded RNA, OAS1 is an enzyme that plays a crucial role in innate antiviral defiance. When OAS1 is activated, it catalyzes the oligomerization of ATP into 2-5A and activates latent RNase L. In turn, it degrades viral and cellular RNA and blocks protein synthesis [7]. Further, it has been reported that extracellular OAS1 can enter cells independent of RNase L and directly inhibit viral proliferation without activating the known antiviral signaling pathways. It also has strong in vivo and in vitro antiviral activity [30]. Therefore, this study proposes that women with GDM are susceptible to viral infection during pregnancy due to low immune function, resulting in the release of OAS1 protein into the extracellular matrix to act on the corresponding receptor. This in turn inhibits the cell's RNA synthesis, leading to protein synthesis disorders. Additionally, the above is consistent the results obtained from the GO analysis in the present study, that is, DEGs mainly enriched in extracellular regions mediate receptor ligand activity as well as protein interactions.
IFIT1 is one of the upregulated genes in this study and the first identified interferon-stimulated gene (ISG). The interferon-induced protein with tetratricopeptide repeats (IFIT) family—which includes four members, IFIT1, IFIT2, IFIT3, and IFIT5—is an important component of the antiviral immune response. In fact, these genes are mostly silent in the majority of cell types but are greatly induced when the body is affected by a virus infection, an increase of interferons, and so on [13]. However, a previous study found that IFIT1 is a positive regulator of the IFNB1 gene and antiviral IFN gene program. In contrast, it negatively regulates the expression of the pro-inflammatory cytokine TNF in genome-wide siRNA screening. Further, higher levels of TNF have been detected in the placenta of diabetic women, indicating that inflammation and hyperglycemia are responsible for the production of TNF in the full-term placenta [17]. Therefore, according to the results of the GO and KEGG analyses in the present study, it was inferred that IFIT1 plays an important role in inhibiting the increase of inflammatory cytokines such as TNF and IFN, further reducing the continuous chronic inflammatory response in GDM. Besides, with respect to the effect of the induction of IFIT1, some reports proved that it mediates PPIs and the assembly of large protein complexes [14]. This may also be one of the reasons why we can see the DEGs mainly enriched in the collagen-containing extracellular matrix in the GO analysis.
Like IFIT1, ISG15 is also one of the ISGs that functions as an antiviral effector [16]. ISG15 is one of nearly 20 member proteins in the ubiquitin family. The family is divided into ubiquitin and ubiquitin modifications (UBLs), and it plays an indispensable role in regulating cellular activities such as protein stabilization, cell transport, cell cycle, and immune regulation [18].
Further, it is because ISG15 can bind to the IFA receptor firsthand even when there is no preactivated matter that it is considered an outside-in signaling molecule. Additionally, ISG15 can be secreted or released by a variety of cell types, and these secretions of ISG15 are important for activating both congenital and adaptive immune responses. This is because they can stimulate the activity of natural killer cells and T lymphocytes and promote high IFN-ɣ secretion (type II IFN) [26]. Nevertheless, it is unclear how extracellular ISG15 is released, and it is not possible to detect the specific type of cell that releases it. However, some reports suggest that they may be the product of a signal accompanied by type I interferon. The above is not only consistent with our results that the overlapping DEGs principally gather in extracellular regions but also confirm the important role of the extracellular matrix in the development of GDM. Thus, it can be inferred that the secreted ISG15 act on immune cells to further enhance the innate and adaptive immune response, causing changes in the innate immune environment of GDM offspring and, thus, adverse consequences for their growth.
Therefore, the present study analyzed the metabolic influence and mechanism of gestational diabetes on offspring of different genders, which can prevent or reduce the possibility of metabolic diseases among the offspring of mothers with GDM through long-term medical monitoring. However, this study has some limitations. The sample size is too small, and the data is insufficient. Further, the data were obtained from a publicly available database, and it is unclear whether the offspring of these women with GDM have other health problems that can interfere with the outcomes.