Abstract
Maternal gestational diabetes mellitus (GDM) has many adverse effects on the development of offspring. Aberrant DNA methylation is a potential mechanism associated with these effects. However, the effects of GDM on tooth development and the underlying mechanisms have not been thoroughly investigated. In the present study, a GDM rat model was established and incisor labial cervical loop tissue and dental epithelial stem cells (DESCs) were harvested from neonates of diabetic and control dams. GDM significantly suppressed incisor enamel formation and DESCs proliferation and self-renewal in offspring. Gene expression profiles showed that Apex1 was significantly downregulated in the offspring of diabetic dams. In vitro, gain and loss of function analyses showed that APEX1 was critical for DESCs proliferation and self-renewal and Oct4 and Nanog regulation via promoter methylation. In vivo, we confirmed that GDM resulted in significant downregulation of Oct4 and Nanog and hypermethylation of their promoters. Moreover, we found that APEX1 modulated DNA methylation by regulating DNMT1 expression through ERK and JNK signalling. In summary, our data suggest that GDM-induced APEX1 downregulation increased DNMT1 expression, thereby inhibiting Oct4 and Nanog expression, through promoter hypermethylation, resulting in suppression of DESCs proliferation and self-renewal, as well as enamel formation.
Highlights
Maternal gestational diabetes mellitus (GDM) has many adverse effects on the development of offspring
Our results showed that exposure to this environment has dramatic effects on proliferation and self-renewal in offspring dental epithelial stem cells (DESCs), indicating critical APEX1-mediated dysregulation of DNA methylation, and providing novel insights into the mechanisms of DNA methylation-induced reprogramming of tooth development induced by maternal diabetes
We established a maternal gestational diabetes rat model to determine its effects on tooth development in offspring and to study the mechanisms associated with these effects
Summary
Maternal gestational diabetes mellitus (GDM) has many adverse effects on the development of offspring. Gain and loss of function analyses showed that APEX1 was critical for DESCs proliferation and self-renewal and Oct[4] and Nanog regulation via promoter methylation. Our data suggest that GDM-induced APEX1 downregulation increased DNMT1 expression, thereby inhibiting Oct[4] and Nanog expression, through promoter hypermethylation, resulting in suppression of DESCs proliferation and self-renewal, as well as enamel formation. A number of epidemiological studies have demonstrated that in utero exposure to maternal hyperglycaemia, induced by GDM, has detrimental effects on cardiovascular and urinary system development, and is linked to obesity and associated metabolic complications in the offspring[2,3,4,5,6]. The effects of maternal diabetes on tooth development, and the associated underlying mechanisms have not been thoroughly investigated. Whether maternal gestational diabetes modulates tooth morphogenesis in offspring through altered DNA methylation remains largely unknown. To date, there have been few reports on the function of APEX1 in tooth development and pathology
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