Abstract
It is widely accepted that diabetes mellitus impairs placental development, but the mechanism by which the disease operates to impair development remains controversial. In this study, we demonstrated that pregestational diabetes mellitus (PGDM)-induced defects in placental development in mice are mainly characterized by the changes of morphological structure of placenta. The alteration of differentiation-related gene expressions in trophoblast cells rather than cell proliferation/apoptosis is responsible for the phenotypes found in mouse placenta. Meanwhile, excess reactive oxygen species (ROS) production and activated nuclear factor erythroid2-related factor 2 (Nrf2) signalling were observed in the placenta of mice suffering from PGDM. Using BeWo cells, we also demonstrated that excess ROS was produced and Nrf2 signalling molecules were activated in settings characterized by a high concentration of glucose. More interestingly, differentiation-related gene expressions in trophoblast cells were altered when endogenous Nrf2 expression is manipulated by transfecting Nrf2-wt or Nrf2-shRNA. In addition, PGDM interferes with autophagy in both mouse placenta and BeWo cells, implying that autophagy is also involved, directly or indirectly, in PGDM-induced placental phenotypes. Therefore, we revealed that dysfunctional oxidative stress-activated Nrf2 signalling and autophagy are probably responsible for PGDM-induced defects in the placental development of mice. The mechanism was through the interference with differentiation-related gene expression in trophoblast cells.
Highlights
As shown in the literature, pregnant women with either pre-existing diabetes mellitus or gestational diabetes mellitus (GDM) are at higher risk of carrying a fetus with congenital anomalies including phocomelia, cardiac malformations, macrosomia and central nervous system malformations [1,2]
In our examination of the pregnant mice, we found that resorption or intermediate fetal death happened in the presence of high glucose to a greater extent compared with these occurrences among the control groups; this difference was especially obvious during the late gestational stage (control (n 1⁄4 34): 0.06 + 0.02; PDGM (n 1⁄4 18): 0.15 + 0.06, p, 0.05; figure 1a –e)
The predominant reason for fetal resorption is the presence of developmental defects in placenta; we confirmed this in mice with pregestational diabetes mellitus (PGDM) according to the previous reports [7]
Summary
As shown in the literature, pregnant women with either pre-existing diabetes mellitus or gestational diabetes mellitus (GDM) are at higher risk of carrying a fetus with congenital anomalies including phocomelia, cardiac malformations, macrosomia and central nervous system malformations [1,2]. Among the diabetes mellitus-induced congenital malformations, congenital heart disease and anomalies of the nervous system are predominant, posing 3.4 times higher risk and 2.7 times higher risk, respectively [3]. Note that this may be because both the cardiovascular and nervous systems are formed in the early developmental stage, making them more vulnerable to external harmful factors. License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. The exact aetiology and pathogenesis for diabetes mellitus-induced congenital development defects remains controversial
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