Chemoprevention of dibenzo[a,l]pyrene transplacental carcinogenesis in mice born to mothers administered green tea: primary role of caffeine

Abstract

Our laboratory recently developed a mouse model of transplacental induction of lymphoma, lung and liver cancer by the polycyclic aromatic hydrocarbon, dibenzo[a,l]pyrene (DBP). Pregnant B6129SF1 females, bred to 129S1/SvIm males, were treated on day 17 of gestation with an oral dose of 15 mg/kg DBP. Beginning on day 0 of gestation, dams were given (ad lib) buffered water, 0.5% green tea, 0.5% decaffeinated green tea, caffeine or epigallocatechin-3-gallate (EGCG) (both at equivalent concentrations found in tea). The concentration of the teas (and corresponding caffeine and EGCG) was increased to 1.0% upon entering the second trimester, 1.5% at onset of the third trimester and continued at 1.5% until pups were weaned at 21 days of age. Offspring were raised with normal drinking water and AIN93G diet. Beginning at 2 months of age, offspring experienced significant mortalities due to an aggressive T-cell lymphoma as seen in our previous studies. Ingestion of caffeinated, but not decaffeinated, green tea provided modest but significant protection (P = 0.03) against mortality. Caffeine provided a more robust (P = 0.006) protection, but EGCG was without effect. Offspring also developed DBP-dependent lung adenomas. All treatments significantly reduced lung tumor multiplicity relative to controls (P < 0.02). EGCG was most effective at decreasing tumor burden (P = 0.005) by on average over 40% compared with controls. Induction of Cytochrome P450 (Cyp)1b1 in maternal liver may reduce bioavailability of DBP to the fetus as a mechanism of chemoprevention. This is the first demonstration that maternal ingestion of green tea, during pregnancy and nursing, provides protection against transplacental carcinogenesis.

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.…”

“…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).…”

DNA methylation in lung tissues of mouse offspring exposed in utero to polycyclic aromatic hydrocarbons

“…Moreover, B6129SF1/J mice possess an AhR-responsive allele, which makes these mice prone to carcinogenesis induced by PAHs via induction of Cyp1b1 and/or Cyp1a1 (Yu et al, 2006a). Furthermore, the mouse Cyp1b1 protein has the highest activity toward conversion of DBC to the carcinogenic fjord region diol-epoxide (Castro et al, 2008c; Luch et al, 1998). Dams were fed AIN93G (Harlan-Teklad, Madison, WI) during pregnancy and lactation.…”