In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

Abstract

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, B-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. (Cancer Res 2006; 66(2): 755-62)

Fetal MouseCyp1b1and Transplacental Carcinogenesis from Maternal Exposure to Dibenzo(a,l)pyrene

“…A classification scheme (40) devised under the direction of the Mouse Models of Human Cancers Consortium has been published and can be used for comparison with the WHO classification of lymphomas (39). We have, for the first time in any animal model, documented that exposure of pregnant mice to a single dose of a potent PAH, DBP, results in a very aggressive T-cell lymphoma in the offspring beginning at 10 weeks of age (8)(9)(10). Our hypothesis is that maternal transfer to the fetus results in cyp1b1-dependent bioactivation to DBP-(−)-anti-(11R,12S,13S,14R)-dihydrodiol epoxide and other reactive metabolites of DBP in the thymus producing a number of DNA adducts.…”

“…In previous studies, using DBP or 3-methylcholanthrene in models, in which either the dam or the fetus were Ahr "nonresponsive" or "responsive," it was shown that the responsive dam reduced the risk to the fetus apparently by decreasing the bioavailability through enhanced maternal metabolism and clearance (7,8).…”

“…At 10 months of age, any surviving mice were euthanized and necropsied. All procedures for treatment, housing, and euthanasia of the mice used in this study have been approved by the Oregon State University Institutional Animal Care and Use Committee and successfully carried out by the investigators (8)(9)(10). Tissues were fixed in 10% formalin, stained with H&E, and analyzed by light microscopy.…”

“…Tissues were fixed in 10% formalin, stained with H&E, and analyzed by light microscopy. We previously identified the lymphoma to be a T-cell lymphoblastic lymphoma and the lung tumors as hyperplasia, adenoma, adenoma with progression, and carcinoma; the liver tumors were identified as foci and adenoma (8).…”

“…At 10 months, the offspring exhibited a 100% incidence of lung adenomas and carcinomas and most of the males had liver lesions as well (8)(9)(10).…”