Although the heavy metal pollutant cadmium (Cd) is a well known teratogen, the mechanism behind Cd mediated teratogenicity is still unclear and it mainly targets the bone development. Previously we and other groups reported on the protective role of nitric oxide (NO), a key signaling molecule in the embryonic developmental process, against thalidomide and other teratogenic assaults also NO is considered to be a vital signaling molecule in the regulation of bone formation. The objective of this study was to investigate the effects of Cd on the mechanistic interplay between reactive oxygen species (ROS) and NO signaling in the developing embryo. Chick embryonic model was used to determine the time and dose dependent effects of Cd and NO recovery against Cd assault. The effects of Cd and NO recovery on the developing embryos were assessed by morphometric analysis using alcian blue and benzidine staining and various angiogenic assays. ROS and NO, levels were measured using ultrasensitive oxygen and NO electrodes respectively. Results showed that Cd treatment during early development caused multiple birth defects, with more frequency of bone related defects such as, micromelia and exencephaly in chick embryos. Exposure to Cd suppressed endogenous NO level and cGMP signaling, inhibiting angioblast activation and subsequently impairing yolk sac vascular development. Furthermore Cd induced superoxide and lipid peroxidation mediated activation of pro apoptotic markers p21 and p53 on developing embryo. Cd also caused down-regulation of FOXO1 and activation of FOXO3 and caspase 3 resulting in apoptosis. Addition of exogenous NO via a NO donor was able to blunt Cd mediated effects and restore normal embryo development. In conclusion, Cd mediated embryopathy occurs via impairing NO-cGMP signaling and inducing oxidative stress and activation of apoptotic pathways. Supplementation of exogenous NO via NO donor negates Cd mediated effects and protects the developing embryo.
17 May 2014 - 20 May 2014