Valentine Holly, Amarnath Kalyani, Amarnath Venkataraman, Li Weihua, Ding Xuncheng, Valentine William M, Ichihara Gaku
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2561, USA.
Toxicol Sci. 2007 Aug;98(2):427-35. doi: 10.1093/toxsci/kfm126. Epub 2007 May 21.
1-Bromopropane (1-BP), an alternative to ozone-depleting solvents, is a neuro and reproductive toxicant in animals and humans. In this study, the dose responses for urinary AcPrCys and S-propylcysteine (PrCys) adducts on globin and neurofilaments were determined as a function of 1-BP exposure level and duration in the rat; and globin PrCys adducts and urinary AcPrCys were quantified in samples obtained from workers in a 1-BP production facility. Rats were exposed to 1-BP by inhalation for 2 weeks at 0, 50, 200, or 800 ppm and to 1-BP at 0 or 50 ppm for 4 weeks. After the 4-week exposures ended, half of the animals were euthanized immediately and half euthanized 8 days later. Urinary AcPrCys was measured using liquid chromatography-tandem mass spectrometry (LC/MS/MS) and gas chromatograph-mass spectrometry (GC/MS); and PrCys adducts were determined on globin and neurofilaments using LC/MS/MS. In rats, PrCys adduct and urinary AcPrCys levels demonstrated a linear dose response relative to exposure level. PrCys globin adducts demonstrated a linear cumulative dose response over the 4-week exposure period. Elimination of AcPrCys appeared biphasic with detectable levels still present in urine up to 8 days postexposure. A significant increase in globin PrCys adducts was observed in the 1-BP workers relative to control workers; and urinary AcPrCys increased with increasing 1-BP ambient exposure levels. The results of these studies demonstrate the ability of 1-BP to covalently modify proteins in vivo and support the potential of urinary AcPrCys and globin PrCys adducts to serve as biomarkers of 1-BP exposure in humans.
1-溴丙烷（1-BP）作为一种消耗臭氧层溶剂的替代品，对动物和人类具有神经毒性和生殖毒性。在本研究中，测定了大鼠体内尿中N-乙酰-S-丙基半胱氨酸（AcPrCys）和S-丙基半胱氨酸（PrCys）与珠蛋白和神经丝的加合物的剂量反应，该反应是1-BP暴露水平和暴露持续时间的函数；并对从一家1-BP生产工厂的工人采集的样本中的珠蛋白PrCys加合物和尿中AcPrCys进行了定量分析。大鼠通过吸入分别暴露于0、50、200或800 ppm的1-BP环境中2周，以及暴露于0或50 ppm的1-BP环境中4周。在4周暴露期结束后，一半动物立即实施安乐死，另一半在8天后实施安乐死。使用液相色谱-串联质谱法（LC/MS/MS）和气相色谱-质谱法（GC/MS）测定尿中AcPrCys；并使用LC/MS/MS测定珠蛋白和神经丝上的PrCys加合物。在大鼠中，PrCys加合物和尿中AcPrCys水平相对于暴露水平呈线性剂量反应。在4周暴露期内，珠蛋白PrCys加合物呈线性累积剂量反应。AcPrCys的消除呈现双相性，暴露后8天内尿中仍可检测到其水平。与对照组工人相比，1-BP生产工厂的工人珠蛋白PrCys加合物显著增加；并且尿中AcPrCys随着1-BP环境暴露水平的增加而升高。这些研究结果证明了1-BP在体内共价修饰蛋白质的能力，并支持尿中AcPrCys和珠蛋白PrCys加合物作为人类1-BP暴露生物标志物的潜力。
