Otteneder M, Lutz U, Lutz W K
Department of Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.
Mutat Res. 2002 Mar 20;500(1-2):111-6. doi: 10.1016/s0027-5107(02)00008-8.
Styrene by inhalation had been shown to increase the lung tumor incidence in mice at 20 ppm and higher, but was not carcinogenic in rats at up to 1000 ppm. Styrene-7,8-oxide, the major metabolic intermediate, has weak electrophilic reactivity. Therefore, DNA adduct formation was expected at a low level and a 32P-postlabeling method for a determination of the two regioisomeric 2'-deoxyguanosyl-O6-adducts at the alpha(7)- and beta(8)-positions had been established. The first question was whether DNA adducts could be measured in the rat at the end of the 2 years exposure of a bioassay for carcinogenicity, even though tumor incidence was not increased. Liver samples of male and female CD rats were available for DNA adduct analysis. Adducts were above the limit of detection only in the highest dose group (1000 ppm), with median levels of 9 and 8 adducts per 10(7) nucleotides in males and females, respectively (sum of alpha- and beta-adducts). The result indicates that the rat liver tolerated a relatively high steady-state level of styrene-induced DNA adducts without detectable increase in tumor formation. The second question was whether different DNA adduct levels in the lung of rats and mice could account for the species difference in tumor incidence. Groups of female CD-1 mice were exposed for 2 weeks to 0, 40, and 160 ppm styrene (6h per day; 5 days per week), female CD rats were exposed to 0 and 500 ppm. In none of the lung DNA samples were adducts above a limit of detection of 1 adduct per 10(7) DNA nucleotides. The data indicate that species- and organ-specific tumor induction by styrene is not reflected by DNA adduct levels determined in tissue homogenate. The particular susceptibility of the mouse lung might have to be based on other reactive metabolites and DNA adducts, indirect DNA damage and/or cell-type specific toxicity and tumor promotion.
吸入苯乙烯已被证明在浓度为20 ppm及更高时会增加小鼠肺部肿瘤的发生率，但在高达1000 ppm的浓度下对大鼠无致癌性。苯乙烯-7,8-氧化物是主要的代谢中间体，具有较弱的亲电反应性。因此，预计DNA加合物的形成水平较低，并且已经建立了一种32P后标记法来测定α(7)-和β(8)-位的两种区域异构体2'-脱氧鸟苷-O6-加合物。第一个问题是，在致癌性生物测定的2年暴露结束时，即使肿瘤发生率没有增加，是否能够在大鼠中检测到DNA加合物。有雄性和雌性CD大鼠的肝脏样本可用于DNA加合物分析。仅在最高剂量组（1000 ppm）中，加合物高于检测限，雄性和雌性每10(7)个核苷酸的加合物中位水平分别为9和8（α-和β-加合物之和）。结果表明，大鼠肝脏能够耐受相对较高的苯乙烯诱导的DNA加合物稳态水平，而肿瘤形成没有可检测到的增加。第二个问题是，大鼠和小鼠肺部不同的DNA加合物水平是否可以解释肿瘤发生率的种属差异。将雌性CD-1小鼠组暴露于0、40和160 ppm苯乙烯中2周（每天6小时；每周5天），雌性CD大鼠暴露于0和500 ppm。在所有肺部DNA样本中，加合物均未超过每10(7)个DNA核苷酸1个加合物的检测限。数据表明，组织匀浆中测定的DNA加合物水平并未反映出苯乙烯对不同种属和器官的肿瘤诱导作用。小鼠肺部的特殊易感性可能必须基于其他反应性代谢产物和DNA加合物、间接DNA损伤和/或细胞类型特异性毒性及肿瘤促进作用。
