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Effects of oxidative stress on hyperglycaemia-induced brain malformations in a diabetes mouse model
Ya Jin1, Guang Wang2, Sha-Sha Han1
1Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China.
Insights
Maternal diabetes during pregnancy increases fetal neurodevelopmental defects. This study reveals that Nrf2-regulated antioxidant stress is a key factor in these hyperglycaemia-induced defects.
Area of Science:
- Neuroscience
- Developmental Biology
- Endocrinology
Background:
- Pregestational diabetes mellitus (PGDM) is linked to fetal neurodevelopmental defects.
- The precise mechanisms underlying hyperglycemia-induced neurodevelopmental issues remain unclear.
Purpose of the Study:
- To investigate the impact of maternal hyperglycemia on fetal neurodevelopment.
- To elucidate the role of antioxidant stress and the Nrf2 pathway in these defects.
Main Methods:
- Utilized a streptozotocin-induced diabetes mouse model.
- Assessed neuronal and glial differentiation markers (Tuj-1, GFAP).
- Analyzed apoptosis (TUNEL), proliferation (PCNA), and antioxidant markers (SOD, Nrf2, NQO1, HO1) in fetal brains and cell lines (U87, SH-SY5Y).
Main Results:
- PGDM mice exhibited suppressed neuronal differentiation and slightly promoted glial differentiation.
- Maternal hyperglycemia increased fetal brain apoptosis but not proliferation.
- Increased antioxidant enzyme activity and Nrf2 expression were observed in PGDM fetal brains.
- Down-regulating Nrf2 in neuronal cells affected viability under high glucose conditions.
Conclusions:
- Nrf2-modulated antioxidant stress is a critical mediator of neurodevelopmental defects caused by maternal hyperglycemia.
- Targeting the Nrf2 pathway may offer therapeutic strategies for preventing these complications.
Abstract:
Pregestational diabetes mellitus (PGDM) enhances the risk of fetal neurodevelopmental defects. However, the mechanism of hyperglycaemia-induced neurodevelopmental defects is not fully understood. In this study, several typical neurodevelopmental defects were identified in the streptozotocin-induced diabetes mouse model. The neuron-specific class III beta-tubulin/forkhead box P1-labelled neuronal differentiation was suppressed and glial fibrillary acidic protein-labelled glial cell lineage differentiation was slightly promoted in pregestational diabetes mellitus (PGDM) mice. Various concentrations of glucose did not change the U87 cell viability, but glial cell line-derived neurotrophic factor expression was altered with varying glucose concentrations. Mouse maternal hyperglycaemia significantly increased Tunel(+) apoptosis but did not dramatically affect PCNA(+) cell proliferation in the process. To determine the cause of increased apoptosis, we determined the SOD activity, the expression of Nrf2 as well as its downstream anti-oxidative factors NQO1 and HO1, and found that all of them significantly increased in PGDM fetal brains compared with controls. However, Nrf2 expression in U87 cells was not significantly changed by different glucose concentrations. In mouse telencephalon, we observed the co-localization of Tuj-1 and Nrf2 expression in neurons, and down-regulating of Nrf2 in SH-SY5Y cells altered the viability of SH-SY5Y cells exposed to high glucose concentrations. Taken together, the data suggest that Nrf2-modulated antioxidant stress plays a crucial role in maternal hyperglycaemia-induced neurodevelopmental defects.
