To the editor—We read with interest the findings of Parman and colleagues regarding the etiology of thalidomide-induced embryopathy1. The authors suggest that excess reactive oxygen species (ROS) may be involved in the teratogenic process of thalidomide. Their conclusions are based on increased levels of DNA damage in thalidomide-exposed rabbit embryos, concomitant with induction of embryonic developmental damage. Pre-treatment of the mother with the anti-oxidant α-phenyl-N-t-butylnitrone was shown to reduce embryonic dysmorphogenesis. In earlier studies, the authors presented evidence suggesting that excess ROS may be involved in the induction of phenytoin-associated congenital malformations2, and others have suggested a role for ROS in ethanol-induced embryopathy3.
Excess ROS may also be important in the maldevelopment seen in the offspring of diabetic mothers. This idea, has been substantiated by in vivo demonstrations of diminished dysmorphogenesis in the offspring of diabetic rodents given dietary antioxidative agents, such as butylated hydroxytoluene4, vitamin E (ref. 5), vitamin C (ref. 6) and lipoic acid7. Pregnant diabetic mice transgenic for Sod1 show fewer embryo malformations than non-transgenic pregnant diabetic controls8. It has been proposed further that oxidative stress in embryos exposed to a diabetic environment may be the result of increased levels of the iso-prostane 8-epi-PGF2 in the embryos9. Also, the fact that high-amplitude mitochondrial swelling in embryonic neuroectoderm of these embryos10 is diminished by anti-oxidative treatment of the mother11 suggests the presence of an embryonic ROS imbalance, with conceivable consequences for the rate of apoptosis in susceptible cell lineages in the embryo12.
Finally, just as in thalidomide teratogenicity, the fetuses and embryos of diabetic rodents have increased rates of DNA damage13,14, suggesting the possibility of a common teratological pathway involving altered expression of genes under the control of transcription factors sensitive to oxidative stress. Investigations of diabetic pregnancies have identified candidate genes, including catalase15 and cyclooxygenase-2 (ref. 9).
These intriguing genetic and biochemical relationships associated with teratological process(es) demand further study. The effect of excessive ROS on embryogenesis may emerge as a more general mechanism in teratogenesis than previously thought.
References
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Yang, X., Borg, L.A.H., Simán, C.M. & Eriksson, U.J. Maternal antioxidant treatments prevent diabetes-induced alterations of mitochondrial morphology in rat embryos. Anat. Rec. 251, 303–315 (1998).
Forsberg, H., Eriksson, U.J. & Welsh, N. Apoptosis in embryos of diabetic rats. Pharmacol. Toxicol. 83, 104–111 (1998).
Lee, A.T., Plump, A., DeSimone, C., Cerami, A. & Bucala, R. A role for DNA mutations in diabetes-associated teratogenesis in transgenic embryos. Diabetes 44, 20–24 (1995).
Lee, A.T., Reis, D. & Eriksson, U.J. Hyperglycemia induced embryonic dysmorphogenesis correlates with genomic DNA mutation frequency in vitro and in vivo. Diabetes 48, 371–376 (1999).
Cederberg, J. & Eriksson, U.J. Decreased catalase activity in malformation-prone embryos of diabetic rats. Teratology 56, 350–357 (1997).
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Eriksson, U. Oxidative DNA damage and embryo development. Nat Med 5, 715 (1999). https://doi.org/10.1038/10420
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DOI: https://doi.org/10.1038/10420
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