Yu Zhen, Loehr Christiane V, Fischer Kay A, Louderback Mandy A, Krueger Sharon K, Dashwood Roderick H, Kerkvliet Nancy I, Pereira Clifford B, Jennings-Gee Jamie E, Dance Stephanie T, Miller Mark Steven, Bailey George S, Williams David E
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-7301, USA.
Cancer Res. 2006 Jan 15;66(2):755-62. doi: 10.1158/0008-5472.CAN-05-3390.
Lymphoma and leukemia are the most common cancers in children and young adults; in utero carcinogen exposure may contribute to the etiology of these cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), was given to pregnant mice (15 mg/kg body weight, gavage) on gestation day 17. Significant mortalities in offspring, beginning at 12 weeks of age, were observed due to an aggressive T-cell lymphoblastic lymphoma. Lymphocytes invaded numerous tissues. All mice surviving 10 months, exposed in utero to DBP, exhibited lung tumors; some mice also had liver tumors. To assess the role of the aryl hydrocarbon receptor (AHR) in DBP transplacental cancer, B6129SF1/J (AHR(b-1/d), responsive) mice were crossed with strain 129S1/SvIm (AHR(d/d), nonresponsive) to determine the effect of maternal and fetal AHR status on carcinogenesis. Offspring born to nonresponsive mothers had greater susceptibility to lymphoma, irrespective of offspring phenotype. However, when the mother was responsive, an AHR-responsive phenotype in offspring increased mortality by 2-fold. In DBP-induced lymphomas, no evidence was found for TP53, beta-catenin, or Ki-ras mutations but lung adenomas of mice surviving to 10 months of age had mutations in Ki-ras codons 12 and 13. Lung adenomas exhibited a 50% decrease and a 35-fold increase in expression of Rb and p19/ARF mRNA, respectively. This is the first demonstration that transplacental exposure to an environmental PAH can induce a highly aggressive lymphoma in mice and raises the possibility that PAH exposures to pregnant women could contribute to similar cancers in children and young adults.
淋巴瘤和白血病是儿童和青年中最常见的癌症；子宫内接触致癌物可能与这些癌症的病因有关。在妊娠第17天，给怀孕小鼠灌胃多环芳烃（PAH）二苯并[a,l]芘（DBP）（15毫克/千克体重）。观察到后代从12周龄开始出现显著死亡，原因是侵袭性T细胞淋巴母细胞淋巴瘤。淋巴细胞侵入许多组织。所有在子宫内接触DBP并存活10个月的小鼠都出现了肺部肿瘤；一些小鼠还患有肝脏肿瘤。为了评估芳烃受体（AHR）在DBP经胎盘致癌中的作用，将B6129SF1/J（AHR(b-1/d)，有反应）小鼠与129S1/SvIm品系（AHR(d/d)，无反应）杂交，以确定母体和胎儿AHR状态对致癌作用的影响。无论后代表型如何，无反应母亲所生的后代对淋巴瘤更易感。然而，当母亲有反应时，后代中AHR有反应的表型使死亡率增加了2倍。在DBP诱导的淋巴瘤中，未发现TP53、β-连环蛋白或Ki-ras突变的证据，但存活至10个月龄的小鼠的肺腺瘤在Ki-ras密码子12和13处有突变。肺腺瘤中Rb和p19/ARF mRNA的表达分别下降了50%和增加了35倍。这是首次证明经胎盘接触环境PAH可在小鼠中诱发高度侵袭性淋巴瘤，并增加了孕妇接触PAH可能导致儿童和青年患类似癌症的可能性。
