Abstract：
BACKGROUND: Hexavalent chromium (Cr(Ⅵ)) is classified as a group 1 human carcinogen and increases the risk of lung cancer. Non-coding RNAs (ncRNAs) have key regulatory roles in lung cancer, but less is known about their relation to Cr(Ⅵ) exposure.
OBJECTIVE: We aimed to 1) measure the expression of lung cancer-related circulating ncRNAs in exposed workers and controls; 2) assess associations between ncRNAs expression and Cr concentrations in red blood cells (RBC) and urine; and 3) evaluate correlations between the ncRNAs.
METHODS: The study included 111 Cr(VI) exposed workers and 72 controls recruited from the SafeChrom project. Cr concentrations were measured in RBC (biomarker of long-term exposure) and urine (biomarker of short-term exposure) samples. Long ncRNA (lncRNA) and microRNA (miRNA) were extracted from plasma followed by deoxyribonuclease treatment, complementary DNA synthesis, and quantitative real-time polymerase chain reaction using target-specific assays for three lncRNAs (H19, MALAT1, NORAD), and four miRNAs (miR-142-3p, miR-15b-5p, miR-3940-5p, miR-451a).
RESULTS: Expression levels of lncRNAs MALAT1 and NORAD, and all four miRNAs, were significantly lower in Cr(VI) exposed workers compared with controls, and correlated significantly with RBC-Cr concentrations (rS = -0.16 to -0.38). H19 was non-significantly increased in exposed workers but significantly correlated with miR-142-3p (rS = -0.33) and miR-15b-5p (rS = -0.30), and NORAD was significantly positively correlated with all four miRNAs (rS = 0.17 to 0.46). In multivariate regression models adjusting for confounders, expressions of lncRNAs MALAT1 and NORAD and all miRNAs were still significantly lower in the exposed group compared with controls, and the expression decreased with increasing RBC-Cr concentrations.
CONCLUSIONS: Cr(VI) exposure was inversely and in a dose-response manner associated with the expression of circulating non-coding RNA, which suggests ncRNAs as potential biomarkers for Cr(VI)-induced toxicity. Correlations between miRNAs and lncRNAs suggest that they participate in the same lncRNA-miRNA-messenger RNA regulatory axes, which may play important roles in Cr(VI) carcinogenesis.
OBJECTIVE: We aimed to 1) measure the expression of lung cancer-related circulating ncRNAs in exposed workers and controls; 2) assess associations between ncRNAs expression and Cr concentrations in red blood cells (RBC) and urine; and 3) evaluate correlations between the ncRNAs.
METHODS: The study included 111 Cr(VI) exposed workers and 72 controls recruited from the SafeChrom project. Cr concentrations were measured in RBC (biomarker of long-term exposure) and urine (biomarker of short-term exposure) samples. Long ncRNA (lncRNA) and microRNA (miRNA) were extracted from plasma followed by deoxyribonuclease treatment, complementary DNA synthesis, and quantitative real-time polymerase chain reaction using target-specific assays for three lncRNAs (H19, MALAT1, NORAD), and four miRNAs (miR-142-3p, miR-15b-5p, miR-3940-5p, miR-451a).
RESULTS: Expression levels of lncRNAs MALAT1 and NORAD, and all four miRNAs, were significantly lower in Cr(VI) exposed workers compared with controls, and correlated significantly with RBC-Cr concentrations (rS = -0.16 to -0.38). H19 was non-significantly increased in exposed workers but significantly correlated with miR-142-3p (rS = -0.33) and miR-15b-5p (rS = -0.30), and NORAD was significantly positively correlated with all four miRNAs (rS = 0.17 to 0.46). In multivariate regression models adjusting for confounders, expressions of lncRNAs MALAT1 and NORAD and all miRNAs were still significantly lower in the exposed group compared with controls, and the expression decreased with increasing RBC-Cr concentrations.
CONCLUSIONS: Cr(VI) exposure was inversely and in a dose-response manner associated with the expression of circulating non-coding RNA, which suggests ncRNAs as potential biomarkers for Cr(VI)-induced toxicity. Correlations between miRNAs and lncRNAs suggest that they participate in the same lncRNA-miRNA-messenger RNA regulatory axes, which may play important roles in Cr(VI) carcinogenesis.
摘要：
背景：六价铬（Cr（Ⅵ））被归类为人类第1类致癌物，并增加患肺癌的风险。非编码RNA（ncRNAs）在肺癌中具有关键的调节作用，但对它们与Cr(Ⅵ)暴露的关系知之甚少。
目的：我们的目的是1）测量暴露工人和对照组中肺癌相关循环ncRNAs的表达；2）评估ncRNAs表达与红细胞（RBC）和尿液中Cr浓度之间的关联；以及3）评估ncRNAs之间的相关性。
方法：该研究包括111名接触Cr（VI）的工人和从SafeChrom项目招募的72名对照。在RBC(长期暴露的生物标志物)和尿(短期暴露的生物标志物)样品中测量Cr浓度。从血浆中提取长ncRNA（lncRNA）和microRNA（miRNA），然后用脱氧核糖核酸酶处理，互补DNA合成，和定量实时聚合酶链反应使用靶特异性测定三个lncRNAs（H19，MALAT1，NORAD），和四个miRNA(miR-142-3p，miR-15b-5p,miR-3940-5p,miR-451a）。
结果：lncRNAsMALAT1和NORAD的表达水平，和所有四个miRNA，与对照组相比，接触Cr（VI）的工人明显更低，并且与RBC-Cr浓度显着相关（rS=-0.16至-0.38）。H19在接触工人中没有显着增加，但与miR-142-3p（rS=-0.33）和miR-15b-5p（rS=-0.30）显着相关，NORAD与4种miRNAs均呈显著正相关(rS=0.17~0.46)。在针对混杂因素进行调整的多元回归模型中，与对照组相比，暴露组的lncRNAsMALAT1和NORAD以及所有miRNAs的表达仍然显着降低，表达随RBC-Cr浓度的增加而降低。
结论：Cr（VI）暴露与循环非编码RNA的表达呈相反的剂量反应方式，这表明ncRNAs是Cr(VI)诱导毒性的潜在生物标志物。miRNA和lncRNA之间的相关性表明它们参与相同的lncRNA-miRNA-信使RNA调控轴,可能在Cr(VI)癌变过程中起重要作用。
目的：我们的目的是1）测量暴露工人和对照组中肺癌相关循环ncRNAs的表达；2）评估ncRNAs表达与红细胞（RBC）和尿液中Cr浓度之间的关联；以及3）评估ncRNAs之间的相关性。
方法：该研究包括111名接触Cr（VI）的工人和从SafeChrom项目招募的72名对照。在RBC(长期暴露的生物标志物)和尿(短期暴露的生物标志物)样品中测量Cr浓度。从血浆中提取长ncRNA（lncRNA）和microRNA（miRNA），然后用脱氧核糖核酸酶处理，互补DNA合成，和定量实时聚合酶链反应使用靶特异性测定三个lncRNAs（H19，MALAT1，NORAD），和四个miRNA(miR-142-3p，miR-15b-5p,miR-3940-5p,miR-451a）。
结果：lncRNAsMALAT1和NORAD的表达水平，和所有四个miRNA，与对照组相比，接触Cr（VI）的工人明显更低，并且与RBC-Cr浓度显着相关（rS=-0.16至-0.38）。H19在接触工人中没有显着增加，但与miR-142-3p（rS=-0.33）和miR-15b-5p（rS=-0.30）显着相关，NORAD与4种miRNAs均呈显著正相关(rS=0.17~0.46)。在针对混杂因素进行调整的多元回归模型中，与对照组相比，暴露组的lncRNAsMALAT1和NORAD以及所有miRNAs的表达仍然显着降低，表达随RBC-Cr浓度的增加而降低。
结论：Cr（VI）暴露与循环非编码RNA的表达呈相反的剂量反应方式，这表明ncRNAs是Cr(VI)诱导毒性的潜在生物标志物。miRNA和lncRNA之间的相关性表明它们参与相同的lncRNA-miRNA-信使RNA调控轴,可能在Cr(VI)癌变过程中起重要作用。
