Cadmium-Induced Embryopathy: Nitric Oxide Rescues Teratogenic Effects of Cadmium

Abstract

Although Cadmium (Cd) is a well-known heavy metal pollutant and teratogen, the mechanism behind Cd-mediated teratogenicity remains unknown. Previously, we have reported of the protective role of Nitric oxide (NO), a key signaling molecule in the embryonic developmental process, against Thalidomide-induced teratogenicity. The objective of this study was to obtain a mechanistic in-sight of the antiteratogenic potential of NO against Cd-mediated teratogenicity. To achieve this goal, we first studied the effect of Cd on the vasculature of developing embryos and then we investigated whether Cd mediated its effects by interfering with the redox regulation of NO signaling in the early development milieu. We used a chick embryonic model to determine the time and dose-dependent effects of Cd and NO recovery against Cd assault. The effects of Cd and NO recovery were assessed using various angiogenic assays. Redox and NO levels were also measured. Results demonstrated that exposure to Cd at early stage of development caused multiple birth defects in the chick embryos. Exposure to Cd suppressed endogenous NO levels and cGMP signaling, inhibiting angioblast activation and subsequently impairing yolk sac vascular development. Furthermore, Cd-induced superoxide and lipid peroxidation mediated activation of proapoptotic markers p21 and p53 in the developing embryo. Cd also caused the down-regulation of FOXO1, and up-regulation of FOXO3a and Caspase 3-mediated apoptosis. Addition of exogenous NO through a NO donor was able to blunt Cd-mediated effects and restore normal vascular and embryonic development. In conclusion, Cd-mediated teratogenicity occurs as a result of impaired NO-cGMP signaling, increased oxidative stress, and the activation of apoptotic pathways. Subsequent addition of exogenous NO through NO donor negated Cd-mediated effects and protected the developing embryo.

sFRP4 signalling of apoptosis and angiostasis uses nitric oxide-cGMP-permeability axis of endothelium

“…While Antonova et al [44] reported that preconditioning with low doses of a NO donor could accelerate the repair and maintenance of endothelial integrity via the sGC pathway. Previous reports from our lab group have also shown that treatment with NO donors or cGMP analogs can restore and protect endothelial function, morphology and barrier integrity [26,27,[45][46][47]. Similarly, we noted that addition of NO donor SP or activators of NO/sGC/cGMP activity such as YC-1 (an NO independent activator of sGC), SC (which increases cellular cGMP by PDE inhibition) and 8-Br (cGMP analogue) could blunt sFRP4 mediated effects.…”

“…Similarly, we noted that addition of NO donor SP or activators of NO/sGC/cGMP activity such as YC-1 (an NO independent activator of sGC), SC (which increases cellular cGMP by PDE inhibition) and 8-Br (cGMP analogue) could blunt sFRP4 mediated effects. Previously we have shown that endothelial dysfunction, whether hypoxia-driven or induced by teratogens (cadmium, thalidomide), occurs primarily as a consequence of decreased intercellular NO bioavailability and/or bioactivity and elevated ROS levels, which promotes apoptosis [26,27,[45][46][47]. Superoxide production in EC has been reported to contribute to enhanced permeability of EC membrane [48], particularly as NO is known for its strong affinity to react with superoxide radicals [49] to form peroxynitirite and thereby causing leakiness of the endothelium.…”

Pre‐ and Postnatal Lung Development: An Updated Species Comparison

“…The most plausible explanations point to an increased ROS production and, therefore, increased oxidative stress, increased superoxide and lipid peroxidation and cadmium‐induced lung inflammation (Cormet‐Boyaka et al, ; Song et al, ; Veeriah et al, ). This is underlined by the anti‐teratogenic potential of nitric oxide, glycine as well as zinc against Cd‐mediated teratogenicity (Daston, ; Paniagua‐Castro et al, ; Veeriah et al, ). Furthermore, Cd 2+ displays an inhibitory effect on the placental and fetal uptake of Zn 2+ and Cu 2+ (Holt and Webb, ).…”

Chokeberries (Aronia melanocarpa) and Their Products as a Possible Means for the Prevention and Treatment of Noncommunicable Diseases and Unfavorable Health Effects Due to Exposure to Xenobiotics

“…Occupational exposure to this metal creates also the risk of respiratory system damage (Moitra and others ; Brüning and others ) and may lead to cognitive impairment (Draz and others ; Brüning and others ). Moreover, Cd is a teratogenic and carcinogenic agent (Veeriah and others ; van Maele‐Fabry and others ). It has been recognized that exposure of the general population to this heavy metal in industrialized countries will show an increasing trend in future decades (Järup and Akesson ; Nawrot and others ).…”