Curriculum in Toxicology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Toxicol Appl Pharmacol. 2012 Apr 15;260(2):105-14. doi: 10.1016/j.taap.2012.02.006. Epub 2012 Feb 16.
Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA.
生物标志物的鉴定有助于疾病的诊断和环境暴露所致健康风险的评估。我们假设，暴露于利比角闪石（LA）的大鼠将呈现出独特的血清蛋白质组学特征，这有助于阐明具有流行病学相关性的生物标志物。在四个跨越不同方案和时间性的实验中，健康（Wistar Kyoto，WKY；和 F344）和心血管受损（CVD）大鼠模型（自发性高血压，SH；和 SH 心力衰竭，SHHF）经气管内滴注生理盐水（对照）或 LA。分析了癌症、炎症、代谢综合征（MetS）和急性期反应（APR）的血清生物标志物。所有大鼠品系均表现出α-2-巨球蛋白和α1-酸性糖蛋白的急性增加。在炎症标志物中，脂联素-2 在 WKY、SH 和 SHHF 中诱导，骨桥蛋白仅在 WKY 中诱导。尽管 MetS 生物标志物存在与大鼠品系和年龄相关的变化，但没有 LA 影响的明显证据。在一项研究中，WKY 在 1 个月时仅略有增加癌症标志物间皮素。在每周 4 次 LA 滴注后 1 天或 4 周对 WKY 血清进行定量完整蛋白质组学分析表明，没有氧化蛋白修饰，但 APR 蛋白显著增加。这些蛋白包括丝氨酸蛋白酶抑制剂、载脂蛋白 E、α-2-HS-糖蛋白、t-激肽原 1 和 2、铜蓝蛋白、维生素 D 结合蛋白、血清淀粉样蛋白 P 等，在最后一次 LA 暴露后 1 天增加。无论急性或长期暴露，所有变化在短暂恢复后均是可逆的。因此，LA 暴露会诱导 APR 和全身性炎症生物标志物，这可能对暴露于 LA 的个体的系统性和肺部疾病产生影响。
