Indole-3-carbinol in the maternal diet provides chemoprotection for the fetus against transplacental carcinogenesis by the polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene

Abstract

The fetus and neonate are sensitive targets for chemically induced carcinogenesis. Few studies have examined the risk/benefit of chemoprotective phytochemicals, given in the maternal diet, against transplacental carcinogenesis. In this study, B6129 SF1/J (AHR(b-1/d)) and 129Sv/ImJ (AHR(d/d)) mice were cross-bred. The polycyclic aromatic hydrocarbon, dibenzo[a,l]pyrene (DBP), was administered to pregnant mice (15 mg/kg, gavage) on gestation day 17, and 2000 p.p.m. indole-3-carbinol (I3C), a chemoprotective phytochemical from cruciferous vegetables, was fed to half of the mice from gestation day 9 until weaning. Offspring born to dams fed I3C exhibited markedly fewer mortalities (P< 0.0001). Maternal dietary exposure to I3C also significantly lowered lung tumor multiplicity (P = 0.035) in offspring surviving to 10 months of age. The I3C chemoprotection was independent of either maternal or fetal AHR genotype. The bioavailability of DBP to fetal target tissue was demonstrated by assessing DNA covalent adduction with a (33)P-post-labeling assay. The bioavailability of I3C was determined by dosing a subset of pregnant mice with [(14)C]-I3C. Addition of chemoprotective agents to the maternal diet during pregnancy and nursing may be an effective new approach in reducing the incidence of cancers in children and young adults.

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

“…CYP1B1 has been found to be, at least in part, under epigenetic control (43,44) and it has been suggested that CYP1B1 would make an excellent target for prevention strategies (45). In our previous studies, we showed that the addition of indole-3-carbinol, green tea, or caffeine to the maternal diet during pregnancy and nursing significantly reduced lung cancer multiplicity in 10-month-old offspring from mothers treated with 15 mg/kg DBP (9,10). The results presented in this study provide further evidence that Fig.…”

“…The same nonsynonymous SNPs were also most common in CYP1B1 data from the National Institute of Environmental Health Sciences Environmental Genome Project (50). 9 If humans recapitulate the responses observed here, transplacental exposure to carcinogenic PAHs, such as DBP or benzo(a)pyrene, will lead to lymphoma or lung cancer later in life. The CYP1B1 genetic polymorphism may play a role in the target and severity of the transplacental carcinogenesis.…”

“…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.…”

“…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.…”

“…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).…”