IRCCS SDN, Naples, Italy.
Department of Movement, Human and Health Sciences, Section of Health Sciences, "Foro Italico" University of Rome, Largo Lauro De Bosis 6, 00195, Rome, Italy.
J Endocrinol Invest. 2019 Jun;42(6):727-739. doi: 10.1007/s40618-018-0982-1. Epub 2018 Nov 26.
Cadmium (Cd) is a widespread environmental pollutant that causes alterations in human health acting as endocrine disruptor. Recent data suggest that cardiovascular system might be a contamination target tissue, since Cd is found in atheromatic plaques. Thus, the purpose of this study was to evaluate the consequence of Cd exposure of endothelial cells in vitro to evaluate detrimental effect in vascular system by a potential sex-steroid hormone receptor-dependent mechanism(s).
To this aim, Human Umbilical Vein Endothelial Cells (HUVECs) were cultured and exposed to several concentrations of cadmium chloride (CdCl) for different interval times.
CdCl exposure of HUVECs induced a significant increase of ERβ and Cyp19a1 at both mRNA and protein levels, while a drastic dose-dependent decrease of AR expression level was observed after 24 h of exposure. On the contrary, an increase of PhAR as well as a reduction of PhGSK-3β and PhAKT was detected after 1 h treatment. This effect was consistently reduced by GSK inhibition. Furthermore, CdCl abolished DHT-induced cell proliferation in HUVECs suggesting an antagonist-like effect of Cd on AR-mediated signaling. Remarkable, after 6 h CdCl-treatment, a relevant increase in TNF-α, IL-6 and IL-8 mRNA was observed and this effect was blocked by the presence of an ERβ-selective antagonist. Moreover, Cd-induced TxR1 overexpression, likely, correlated with the activation of p38 MAPK/NF-κB pathway.
In conclusion, our study demonstrates for the first time that Cd alters sex-steroid hormone receptors level and activity likely affecting intracellular signaling linked to a proinflammatory state in endothelial cells. This alteration might possibly lead to endothelial cell injury and vascular dysfunction and could be a mechanism of gender-specific atherogenic damages induced by endocrine disruptors and, thus, induce atherogenic events with increased risk of cardiovascular diseases in individuals exposed to this endocrine disruptor.
镉（Cd）是一种广泛存在的环境污染物，作为内分泌干扰物，会导致人体健康发生变化。最近的数据表明，心血管系统可能是污染的靶组织，因为在动脉粥样斑块中发现了 Cd。因此，本研究旨在评估 Cd 暴露对体外内皮细胞的影响，通过潜在的性甾体激素受体依赖性机制来评估其对血管系统的有害影响。
为此，培养人脐静脉内皮细胞（HUVEC）并使其暴露于不同浓度的氯化镉（CdCl）中不同的时间段。
CdCl 暴露于 HUVEC 中，在 mRNA 和蛋白水平上均显著增加了 ERβ 和 Cyp19a1 的表达，而暴露 24 小时后，AR 的表达水平则呈明显的剂量依赖性下降。相反，在 1 小时处理后，检测到 PhAR 的增加和 PhGSK-3β 和 PhAKT 的减少。这种作用被 GSK 抑制所减少。此外，CdCl 抑制了 DHT 诱导的 HUVEC 增殖，表明 Cd 对 AR 介导的信号具有拮抗剂样作用。值得注意的是，在 CdCl 处理 6 小时后，观察到 TNF-α、IL-6 和 IL-8 的 mRNA 显著增加，这种作用被 ERβ 选择性拮抗剂阻断。此外，Cd 诱导的 TxR1 过表达可能与 p38 MAPK/NF-κB 通路的激活有关。
总之，本研究首次证明 Cd 改变了性甾体激素受体的水平和活性，可能影响内皮细胞中与促炎状态相关的细胞内信号。这种改变可能导致内皮细胞损伤和血管功能障碍，并可能成为内分泌干扰物引起的性别特异性动脉粥样损伤的机制，从而导致暴露于这种内分泌干扰物的个体发生动脉粥样事件，增加患心血管疾病的风险。
