Folic acid and safflower oil supplementation interacts and protects embryos from maternal diabetes-induced damage

Mol Hum Reprod. 2012 May;18(5):253-64. doi: 10.1093/molehr/gar080. Epub 2011 Dec 16.


Maternal diabetes increases the risk of embryo malformations. Folic acid and safflower oil supplementations have been shown to reduce embryo malformations in experimental models of diabetes. In this study we here tested whether folic acid and safflower oil supplementations interact to prevent embryo malformations in diabetic rats, and analyzed whether they act through the regulation of matrix metalloproteinases (MMPs), their endogenous inhibitors (TIMPs), and nitric oxide (NO) and reactive oxygen species production. Diabetes was induced by streptozotocin administration prior to mating. From Day 0.5 of pregnancy, rats did or did not receive folic acid (15 mg/kg) and/or a 6% safflower oil-supplemented diet. Embryos and decidua were explanted on Day 10.5 of gestation for further analysis of embryo resorptions and malformations, MMP-2 and MMP-9 activities, TIMP-1 and TIMP-2 levels, NO production and lipid peroxidation. Maternal diabetes induced resorptions and malformations that were prevented by folic acid and safflower oil supplementation. MMP-2 and MMP-9 activities were increased in embryos and decidua from diabetic rats and decreased with safflower oil and folic acid supplementations. In diabetic animals, the embryonic and decidual TIMPs were increased mainly with safflower oil supplementation in decidua and with folic acid in embryos. NO overproduction was decreased in decidua from diabetic rats treated with folic acid alone and in combination with safflower oil. These treatments also prevented increases in embryonic and decidual lipid peroxidation. In conclusion, folic acid and safflower oil supplementations interact and protect the embryos from diabetes-induced damage through several pathways related to a decrease in pro-inflammatory mediators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Congenital Abnormalities / etiology
  • Congenital Abnormalities / prevention & control
  • Diabetes Mellitus, Experimental / complications*
  • Dietary Supplements*
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / metabolism
  • Embryonic Development / drug effects
  • Female
  • Fetal Resorption / prevention & control
  • Folic Acid / therapeutic use*
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Nitric Oxide / metabolism
  • Pregnancy
  • Pregnancy Outcome
  • Pregnancy in Diabetics*
  • Prenatal Exposure Delayed Effects / drug therapy*
  • Protective Agents / therapeutic use*
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Safflower Oil / therapeutic use*


  • Protective Agents
  • Reactive Oxygen Species
  • Nitric Oxide
  • Safflower Oil
  • Folic Acid
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9