Maternal diabetes increases the risk of caudal regression caused by retinoic acid.
Maternal diabetes increases the risk of congenital malformations in the offspring of affected pregnancies. This increase arises from the teratogenic effect of the maternal diabetic milieu on the developing embryo, although the mechanism of this action is poorly understood. In the present study, we examined whether the vitamin A metabolite retinoic acid (RA), a common drug with well-known teratogenic properties, may interact with maternal diabetes to alter the incidence of congenital malformations in mice. Our results show that when treated with RA, embryos of diabetic mice are significantly more prone than embryos of nondiabetic mice to develop caudal regression, a defect that is highly associated with diabetic pregnancy in humans. By studying the vestigial tail (Wnt-3a(vt)) mutant, we provide evidence that Wnt-3a, a gene that controls the development of the caudal region, is directly involved in the pathogenic pathway of RA-induced caudal regression. We further show that the molecular basis of the increased susceptibility of embryos of diabetic mice to RA involves enhanced downregulation of Wnt-3a expression. This positive interaction between RA and maternal diabetes may have implications for humans in suggesting increased susceptibility to environmental teratogens during diabetic pregnancy.
Chan
Billy W H
BW
Department of Anatomy, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
Chan
Kwok-Siu
KS
Koide
Tsuyoshi
T
Yeung
Sau-Man
SM
Leung
Maran B W
MB
Copp
Andrew J
AJ
Loeken
Mary R
MR
Shiroishi
Toshihiko
T
Shum
Alisa S W
AS
D000014:Abnormalities, Drug-Induced / Q000196:embryology*; D000015:Abnormalities, Multiple / Q000196:embryology / Q000209:etiology* / Q000235:genetics; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000196:embryology; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009154:Mutation; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000150:complications* / Q000196:embryology*; D011506:Proteins / Q000235:genetics; D013723:Teratogens; D014212:Tretinoin / Q000009:adverse effects*; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D011506:Proteins; D013723:Teratogens; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D014212:Tretinoin