Harvilchuck Jill A, Pu Xinzhu, Klaunig James E, Carlson Gary P
School of Health Sciences, Purdue University, West Lafayette, IN 47907-2051, USA.
Toxicology. 2009 Oct 29;264(3):171-8. doi: 10.1016/j.tox.2009.08.001. Epub 2009 Aug 8.
In mice, styrene is hepatotoxic, pneumotoxic, and causes lung tumors. One explanation for the mechanism of toxicity is oxidative stress/damage. Previous studies have shown decreased glutathione levels, linked to increased apoptosis, in lung homogenates and isolated Clara cells 3 h following styrene or styrene oxide (SO) administration or in vitro exposure. The objective of the current studies was to determine what effects styrene and its active metabolites, primarily styrene oxide, had on indicators of oxidative stress and attendant apoptosis in order to understand better the mechanism of styrene-induced toxicity. Three hours following in vitro exposure of Clara cells to styrene or SO there were increases in reactive oxygen species (ROS). Following administration of styrene or styrene oxide ip, increases in ROS, superoxide dismutase (SOD), and 8-hydroxydeoxyguanosine (8-OHdG) formation were observed. Since increases in ROS have been linked to increases in apoptosis ratios of bax/bcl-2, mRNA and protein expression were determined 3-240 h following the administration of styrene and R-styrene oxide (RSO). The bax/bcl-2 mRNA ratio increased 12 and 24 h following R-SO and 120 h following styrene administration. However, the bax/bcl-2 protein ratio was not increased until 240 h following R-SO, and 24 and 240 h following styrene administration. However, only a slight increase in caspase 3 was observed. These results indicated that oxidative stress occurred 3h following styrene or styrene oxide as evidenced by increased ROS and SOD. This increased ROS may be responsible for the increased 8-OHdG formation. Our findings of limited apoptosis in Clara cells following acute exposure to styrene or SO are in agreement with others and may reflect the minimal extent to which apoptosis plays a role in acute styrene toxicity. It is clear, however, that oxidative stress and oxidative effects on DNA are increased following exposure to styrene or styrene oxide, and these may play a role in the lung tumorigenesis in mice.
在小鼠中，苯乙烯具有肝毒性、肺毒性，并可引发肺部肿瘤。毒性机制的一种解释是氧化应激/损伤。先前的研究表明，在给予苯乙烯或环氧苯乙烯（SO）后3小时，或体外暴露后，肺匀浆和分离的克拉拉细胞中的谷胱甘肽水平降低，这与细胞凋亡增加有关。当前研究的目的是确定苯乙烯及其活性代谢产物（主要是环氧苯乙烯）对氧化应激指标和伴随的细胞凋亡有何影响，以便更好地理解苯乙烯诱导毒性的机制。在体外将克拉拉细胞暴露于苯乙烯或SO 3小时后，活性氧（ROS）增加。腹腔注射苯乙烯或环氧苯乙烯后，观察到ROS、超氧化物歧化酶（SOD）和8-羟基脱氧鸟苷（8-OHdG）形成增加。由于ROS增加与bax/bcl-2凋亡率增加有关，因此在给予苯乙烯和R-环氧苯乙烯（RSO）后3至240小时测定mRNA和蛋白质表达。R-SO给药后12小时和24小时以及苯乙烯给药后120小时，bax/bcl-2 mRNA比值增加。然而，bax/bcl-2蛋白质比值直到R-SO给药后240小时以及苯乙烯给药后24小时和240小时才增加。然而，仅观察到半胱天冬酶3略有增加。这些结果表明，苯乙烯或环氧苯乙烯给药3小时后发生氧化应激，表现为ROS和SOD增加。这种增加的ROS可能是8-OHdG形成增加的原因。我们关于急性暴露于苯乙烯或SO后克拉拉细胞中细胞凋亡有限的发现与其他研究结果一致，可能反映了细胞凋亡在急性苯乙烯毒性中所起作用的最小程度。然而，很明显，暴露于苯乙烯或环氧苯乙烯后，氧化应激和对DNA的氧化作用会增加，这些可能在小鼠肺部肿瘤发生中起作用。
