Indole-3-carbinol in the maternal diet provides chemoprotection for the fetus against transplacental carcinogenesis by dibenzo[a,l]pyrene in the B6 129 mouse model : role of the Aryl Hydrocarbon Receptor

Graduation date: 2006Lymphomas and leukemias are the most common cancer in children and young\ud adults and in utero exposure to carcinogens may contribute to the etiology of these\ud cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), was\ud administered to pregnant mice (15 mg/Kg b.w., gavage) on gestation day 17. Significant\ud mortalities in young offspring were observed due to T-cell lymphoma. Lung and liver\ud tumors also were observed in survivors at 10 months of age. To assess the role of the\ud Aryl Hydrocarbon Receptor (AHR), we utilized crosses of B6129SF1/J (responsive) mice\ud with strain 129S1/SvImJ (non-responsive). Offspring born to AHR non-responsive\ud mothers had greater susceptibility to lymphoma, irrespective of offspring genotype.\ud Responsive offspring displayed increased mortality if the mother was responsive. Lung\ud adenomas showed Ki-ras mutations and exhibited a 50% decrease and a 35-fold increase\ud in expression of Rb and p19/ARF mRNA, respectively.\ud To examine the risk/benefit of maternal dietary phytochemical treatment against\ud transplacental cancer, 2000 ppm indole-3-carbinol (I3C) was given to pregnant mice\ud through diet from gestation day 9 till weaning. I3C significantly lowered mortality\ud caused by lymphomas regardless of the maternal genotype, and also reduced lung tumor\ud multiplicity in offspring born to AHR [superscript b-l/d] dams. Distribution of I3C in most maternal\ud and fetal tissues was quantified following a single gavage of [¹⁴C]-I3C to the pregnant\ud mice. DBP-DNA adducts were observed in both maternal and fetal tissues by ³³P\ud postlabeling and HPLC analysis and were modulated by I3C and AHR genotype. I3C\ud also modulated phase I and phase II enzyme protein expression in dams and gene\ud expression in newborn thymus. I3C chemoprotection may involve modification of the\ud bioavailability of DBP to the fetus and/or modulation of gene expression in the fetus as\ud well.\ud This is the first demonstration that transplacental exposure to an environmental PAH\ud can induce a highly aggressive lymphoma in mice. These results raise the possibility that\ud PAH exposures to pregnant women could contribute to similar cancers in children and\ud young adults and, that the addition of chemoprotective agents to the maternal diet may\ud reduce cancer risk among offspring