An embryoprotective role for glucose-6-phosphate dehydrogenase in developmental oxidative stress and chemical...

Area of Science:

• Biochemistry and Molecular Biology
• Developmental Biology
• Genetics and Genomics

Background:

• Glucose-6-phosphate dehydrogenase (G6PD) is a crucial enzyme protecting cells from oxidative stress.
• G6PD deficiency primarily causes red blood cell hemolysis, but its role in development is less understood.
• Oxidative stress during embryonic development can lead to adverse outcomes, including birth defects and fetal death.

Purpose of the Study:

• To investigate the role of G6PD in protecting against endogenous and xenobiotic-induced embryonic oxidative stress.
• To determine if G6PD deficiency impacts prenatal and postnatal survival in mice.
• To assess the effect of G6PD deficiency on teratogenesis induced by phenytoin, a known human teratogen.

Main Methods:

• Utilized genetically modified mice with a hereditary G6PD deficiency.
• Administered phenytoin, a teratogenic drug, to pregnant G6PD-deficient and wild-type dams.
• Assessed prenatal and postnatal survival rates, embryonic DNA oxidation levels, and fetal abnormalities.
• Genotyped fetal resorptions to confirm G6PD deficiency.

Main Results:

• Untreated G6PD-deficient dams exhibited increased fetal resorptions and postnatal mortality.
• Phenytoin treatment of G6PD-deficient dams resulted in significantly higher embryonic DNA oxidation, fetal death, and birth defects compared to controls.
• The majority of fetal resorptions in G6PD-deficient dams were confirmed to be G6PD deficient.

Conclusions:

• G6PD is essential for cytoprotection against both endogenous and drug-induced oxidative stress during embryonic development.
• G6PD deficiency is a critical factor contributing to infertility, in utero and postnatal death, and teratogenesis.
• These findings suggest a broader biological significance of G6PD deficiency beyond hemolysis.