Birth defects in pregestational diabetes: Defect range, glycemic threshold and pathogenesis.

Area of Science:

• Reproductive Medicine
• Developmental Biology
• Endocrinology

Background:

• Pregestational diabetes mellitus (PGD) affects millions of women globally, posing significant risks for maternal and neonatal outcomes.
• PGD is a major cause of structural birth defects, particularly congenital heart defects and central nervous system defects.
• Maternal hyperglycemia is the primary factor mediating teratogenicity in PGD pregnancies.

Purpose of the Study:

• To investigate the molecular mechanisms underlying PGD-induced birth defects.
• To identify potential therapeutic targets for preventing birth defects in PGD pregnancies.

Main Methods:

• Studies in animal models of PGD.
• Analysis of the apoptosis signal-regulating kinase 1 (ASK1)-forkhead transcription factor 3a (FoxO3a)-caspase 8 pathway.
• Investigation of c-Jun-N-Terminal kinase 1/2 (JNK1/2) activation and endoplasmic reticulum (ER) stress.
• Assessment of the effects of gene deletion and ER stress inhibitors.

Main Results:

• PGD induces oxidative stress, leading to dysregulated gene expression and apoptosis in developing organs.
• Activation of the ASK1-FoxO3a-caspase 8 pathway contributes to neural tube defects (NTDs).
• ASK1 activation of JNK1/2 leads to ER stress, further promoting apoptosis and NTDs.
• Deletion of ASK1, JNK1, or JNK2, or inhibition of ER stress, abrogates diabetes-induced apoptosis and reduces NTDs.

Conclusions:

• The ASK1-JNK-ER stress pathway is a critical mediator of PGD-induced teratogenicity.
• Antioxidants targeting this pathway or ER stress inhibitors show potential for preventing PGD-associated birth defects.