Veeriah Vimal, Saran Uttara, Swaminathan Akila, Balaguru Uma Maheswari, Thangaraj Pradeep, Nagarajan Shunmugam, Rajendran Vinoth Kumar, Chatterjee Suvro
*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 *Vascular Biology Laboratory, AU-KBC Research Centre, Anna University, Chennai 600044, India and Department of Biotechnology, Anna University, Chennai 600044, India
Toxicol Sci. 2015 Mar;144(1):90-104. doi: 10.1093/toxsci/kfu258. Epub 2014 Dec 8.
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.
尽管镉（Cd）是一种众所周知的重金属污染物和致畸剂，但其介导致畸性的机制仍不清楚。此前，我们报道了一氧化氮（NO）作为胚胎发育过程中的关键信号分子，对沙利度胺诱导的致畸性具有保护作用。本研究的目的是深入了解NO对镉介导的致畸性的抗致畸潜力的机制。为实现这一目标，我们首先研究了镉对发育中胚胎血管系统的影响，然后研究了镉是否通过干扰早期发育环境中NO信号的氧化还原调节来发挥其作用。我们使用鸡胚模型来确定镉和NO恢复对镉攻击的时间和剂量依赖性影响。使用各种血管生成测定法评估镉和NO恢复的效果。还测量了氧化还原和NO水平。结果表明，在发育早期接触镉会导致鸡胚出现多种出生缺陷。接触镉会抑制内源性NO水平和cGMP信号传导，抑制成血管细胞激活，随后损害卵黄囊血管发育。此外，镉诱导的超氧化物和脂质过氧化介导了发育中胚胎促凋亡标志物p21和p53的激活。镉还导致FOXO1下调，FOXO3a上调以及Caspase 3介导的细胞凋亡。通过NO供体添加外源性NO能够减弱镉介导的影响，并恢复正常的血管和胚胎发育。总之，镉介导的致畸性是由于NO-cGMP信号受损、氧化应激增加和凋亡途径激活所致。随后通过NO供体添加外源性NO可消除镉介导的影响并保护发育中的胚胎。
