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* Department of Pharmacology, University of Toronto, Medical Sciences Building, Toronto Ontario, Canada M5S 1A8;
Department of Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8;
Department of Molecular and Medical Genetics, and Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada M5S 1A8; and
§ Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2
1Correspondence: Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2. E-mail: pg.wells{at}utoronto.ca
The primary recognized health risk from common deficiencies in glucose-6-phosphate dehydrogenase (G6PD), a cytoprotective enzyme for oxidative stress, is red blood cell hemolysis. Here we show that litters from untreated pregnant mutant mice with a hereditary G6PD deficiency had increased prenatal (fetal resorptions) and postnatal death. When treated with the anticonvulsant drug phenytoin, a human teratogen that is commonly used in pregnant women and causes embryonic oxidative stress, G6PD-deficient dams had higher embryonic DNA oxidation and more fetal death and birth defects. The reported G6PD gene mutation was confirmed and used to genotype fetal resorptions, which were primarily G6PD deficient. This is the first evidence that G6PD is a developmentally critical cytoprotective enzyme for both endogenous and xenobiotic-initiated embryopathic oxidative stress and DNA damage. G6PD deficiencies accordingly may have a broader biological relevance as important determinants of infertility, in utero and postnatal death, and teratogenesis.—Nicol, C. J., Zielenski, J., Tsui, L.-C., Wells, P. G. An embryoprotective role for glucose-6-phosphate dehydrogenase in developmental oxidative stress and chemical teratogenesis.
Key Words: reactive oxygen species • development • birth defects • phenytoin • human risk
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