title: 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.
authors.affiliation: *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India.
authors.forename: Vimal
authors.initials: V
authors.lastname: Veeriah
authors.affiliation: *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India.
authors.forename: Uttara
authors.initials: U
authors.lastname: Saran
authors.affiliation: *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India.
authors.forename: Akila
authors.initials: A
authors.lastname: Swaminathan
authors.affiliation: *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India.
authors.forename: Uma Maheswari
authors.initials: UM
authors.lastname: Balaguru
authors.affiliation: *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Thangaraj
authors.affiliation: *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India.
authors.forename: Shunmugam
authors.initials: S
authors.lastname: Nagarajan
authors.affiliation: *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India.
authors.forename: Vinoth Kumar
authors.initials: VK
authors.lastname: Rajendran
authors.affiliation: *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India soovro@yahoo.ca.
authors.forename: Suvro
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D019256:Cadmium Chloride / Q000633:toxicity*; D002478:Cells, Cultured; D002642:Chick Embryo; D006152:Cyclic GMP / Q000378:metabolism; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental; D015227:Lipid Peroxidation / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity*; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D020030:Nitric Oxide Donors; D013723:Teratogens; D009569:Nitric Oxide; D006152:Cyclic GMP; D019256:Cadmium Chloride
keywords: cadmium; embryopathy; nitric oxide; nitric oxide donor; redox stress