Castro David J, Baird William M, Pereira Clifford B, Giovanini Jack, Löhr Christiane V, Fischer Kay A, Yu Zhen, Gonzalez Frank J, Krueger Sharon K, Williams David E
Department of Environmental and Molecular Toxicology, Oregon State University, ALS 1007, Corvallis, OR 97331-7301, USA.
Cancer Prev Res (Phila). 2008 Jul;1(2):128-34. doi: 10.1158/1940-6207.CAPR-07-0004. Epub 2008 Mar 19.
Dibenzo(a,l)pyrene (DBP) is among the most potent carcinogenic polycyclic aromatic hydrocarbons. Previously, we showed that DBP administration to pregnant mice resulted in high mortality of offspring from an aggressive T-cell lymphoma. All mice that survive to 10 months of age exhibit lung tumors with high multiplicity. Recombinant cytochrome P450 (cyp) 1b1 from mice and the homologue 1B1 in humans exhibit high activity toward the metabolic activation of DBP. Targeted disruption of the cyp1b1 gene protects against most DBP-dependent cancers. Mice heterozygous for the disrupted cyp1b1 allele were used to examine the effect of cyp1b1 gene dosage on DBP transplacental carcinogenesis. Dams were treated with 1 or 15 mg/kg of DBP or 50 mg/kg of benzo(a)pyrene. Cyp1b1-null offspring did not develop lymphoma, whereas wild-type and heterozygous siblings, born to dams given the high dose of DBP, exhibited significant mortalities between 10 and 30 weeks of age. At 10 months, all groups had lung adenomas or carcinomas [9.5%, 40.3%, 25.6%, and 100% incidences for controls, benzo(a)pyrene, 1 and 15 mg/kg DBP, respectively]. Cyp1b1 status did not alter benzo(a)pyrene-dependent carcinogenesis. At 1 mg/kg DBP, cyp1b1 status altered the incidence of lung tumors (19.0, 27.8, and 28.6% for nulls, heterozygous, and wild-type, respectively). At 15 mg/kg, tumor multiplicities in cyp1b1 wild-type (9.3) and heterozygous (9.5) offspring were nearly twice that of cyp1b1-null siblings (5.0). These data confirm that cyp1b1 bioactivation of DBP occurs in fetal target tissues, following transplacental exposure, with the thymus and lung as primary and secondary targets, respectively.
二苯并（a，l）芘（DBP）是最具致癌性的多环芳烃之一。此前，我们发现给怀孕小鼠施用DBP会导致侵袭性T细胞淋巴瘤的后代出现高死亡率。所有存活至10个月大的小鼠都表现出高多发性的肺部肿瘤。来自小鼠的重组细胞色素P450（cyp）1b1和人类中的同源物1B1对DBP的代谢活化表现出高活性。cyp1b1基因的靶向破坏可预防大多数依赖DBP的癌症。利用cyp1b1等位基因破坏的杂合小鼠来研究cyp1b1基因剂量对DBP经胎盘致癌作用的影响。给母鼠分别施用1或15 mg/kg的DBP或50 mg/kg的苯并（a）芘。cyp1b1基因缺失的后代未发生淋巴瘤，而给予高剂量DBP的母鼠所生的野生型和杂合子同胞在10至30周龄之间出现了显著的死亡率。在10个月时，所有组都有肺腺瘤或癌[对照组、苯并（a）芘组、1和15 mg/kg DBP组的发病率分别为9.5%、40.3%、25.6%和100%]。cyp1b1状态未改变苯并（a）芘依赖的致癌作用。在1 mg/kg DBP时，cyp1b1状态改变了肺部肿瘤的发病率（cyp1b1基因缺失、杂合子和野生型的发病率分别为19.0%、27.8%和28.6%）。在15 mg/kg时，cyp1b1野生型（9.3）和杂合子（9.5）后代的肿瘤多发性几乎是cyp1b1基因缺失同胞（5.0）的两倍。这些数据证实，经胎盘暴露后，DBP的cyp1b1生物活化发生在胎儿靶组织中，胸腺和肺分别为主要和次要靶器官。
