Exposure during pregnancy and lactation to chemicals in the environment, including tobacco smoke, has been associated with increases in incidences of disease, malformations or behavior in offspring (23
). A number of chemicals have been shown to be transplacental carcinogens in rodent models (reviewed in refs 32
) and epidemiology studies suggest that this phenomenon occurs in exposed human populations as well (23
PAHs are formed from the incomplete combustion of organic materials including the burning of coal, petroleum products or tobacco (reviewed in ref. 39
) and have been listed as human carcinogens by international agency for research on cancer (40
). Increasing energy requirements, especially in countries such as China, are resulting in greater use of coal for energy production; indeed, China derives 70% of its energy from burning coal and the consumption is greater than the USA, European Union and Japan combined (41
). In recent years, Chinese physicians have noted an increased incidence of diseases, which they associate with increased fuel emission (44
). The USA derives ~50% of its energy from coal. China and the USA also lead the world in automobile use, another important source of environmental PAHs. With respect to environmental exposure to PAHs in the USA, it should also be noted that emissions from China reach the USA west coast in ~6 days from the point of origin, during which they undergo a process of ‘aging’, reacting with sulfur, oxygen and nitrogen to yield more genotoxic PAH derivatives (49
The fetus and the neonate are at increased risk from the toxicological effects of PAHs and exposure of women who are of childbearing age and women known to be pregnant or nursing should be of concern. We developed a mouse model in which a single treatment with DBP, a few days prior to parturition, produced a severe T-cell lymphoma between 3 and 6 months of age in offspring (17
). If the mice do not succumb to the lymphoma, 100% develop multiple lung tumors and the majority of males also exhibit liver tumors (17
). Utilizing Cyp1b1-null mice, we demonstrated that DBP-induced transplacental lymphoma mortality is dependent upon Cyp1b1 expression (18
). In the human fetus, as in mice, the thymus exhibits the highest expression of CYP1B1 of any organ during late gestation, and among all CYP isoforms, CYP1B1 has the highest activity toward the conversion of DBP to carcinogenic metabolites (51
We further developed this model for the study of transplacental chemoprevention by dietary agents. Feeding pregnant and lactating mice I3C (20
), or providing green tea or caffeine in the drinking water (21
), resulted in significant protection for offspring against DBP-dependent T-cell lymphoma mortality and lung tumor multiplicity. One caveat with this model, with respect to statistical analysis of the effect of chemopreventive agents on lung tumors, is the fact that, as many mice die at an early age from lymphoma, we are not statistically assessing a true representative population. In order to assess transplacental chemoprevention efficacy in lung without the confounding lymphoma mortality, we would have to conduct the studies in a different strain such as the A/J mouse. We find this remarkable given that, once weaned, offspring were never exposed to the chemopreventive agent. Therefore, all the chemopreventive benefits had to be from in utero
exposure and/or through breast milk. The lymphoma is fatal to mice corresponding in human age to a young adult, with lung tumors developing approximately at the equivalent of human middle age. Thus, modification of the mother's diet during pregnancy (and perhaps lactation) may provide long-term protection from chemical carcinogenesis following in utero
exposure, to middle age and beyond.
Previously, we demonstrated the chemopreventive potential of both CHL and Chl in the trout model and in the rat with AFB1
and DBP as the carcinogen (4
). A preliminary clinical intervention trial in China, where dietary AFB1
exposure is high and HCC represents the major cause of cancer mortality, showed significant protective effects of CHL tablets taken orally at mealtime (14
). Results to date point to the importance of simultaneous coadministration of CHL with the carcinogen, supporting the complexation theory for chemoprevention (11
). Unpublished data in human volunteers given ultralow doses of AFB1
in studies employing accelerator mass spectrometry demonstrated a marked reduction in carcinogen bioavailability when coadministered with CHL or Chl (Bailey et al.
, unpublished data). These results do not exclude additional potential mechanisms of CHL chemoprevention, including modifications of carcinogen-metabolizing enzymes (52
). The study in China documented that some CHL was systemically bioavailable in humans (53
) and oral CHL was capable of inhibiting PAH-induced skin cancer in mice when the carcinogen was applied topically (54
In our mouse model of transplacental cancer, coadministration of CHL provided marked protection against DBP-dependent T-cell lymphoma mortality and lung tumor burden. By design, CHL, Chl and freeze-dried spinach were incorporated into the synthetic AIN93G diet to test for possible systemic effects on tumor development. As mice are nocturnal, most diet would be consumed at night, and there would be little if any agent left in the stomach to interfere with DBP uptake when it was administered hours later. The results point to the importance of complexation as a mechanism of CHL chemoprevention, and presumably also for Chl. The latter possibility remains to be confirmed since we did not include a group with Chl coadministration. However, the results also do not exclude a transient effect, such as inhibition of phase I- or phase II xenobiotic-metabolizing enzymes, or epigenetic mechanisms of chemoprevention, such as alterations in DNA methyl transferase or histone deacetylase, that might return to baseline when DBP dosing took place. In a similar fashion, the administration of CHL by gavage could impact enzymes important for bioactivation/detoxication and potentially exert competitive inhibitory effects at such high concentrations. However, as the major route of PAH exposure (in non-smokers) is dietary (46
), our results would indicate that CHL should be administered with each meal for maximum efficacy, as in the China intervention study (14
). With respect to the impact of the ahr genotype, coadministration of CHL appeared to eliminate genotype sensitivity rather than making it more complex. There is no statistical difference between CHL cotreatment with respect to response by the b-1/d and d/d ahr genotypes.
In summary, CHL, which is inexpensive and appears to lack toxicity in humans, was demonstrated to be effective in the reduction of transplacental cancer risk if given with the PAH carcinogen DBP. This protection was evident even with tumors that appeared well into adult life and is a further example of the ‘fetal basis of disease’. Cancer is the number two cause of death in children/young adults (accidents being number one) and lymphoma/leukemias are the most common of these cancers. Lung cancer is the major cause of cancer mortality in both sexes in the USA and has a relatively poor prognosis (5 year survival rate of 15%). For these reasons, chemopreventive strategies that begin early in development have the potential to reduce the suffering (as well as the health care dollars) associated with cancer, and perhaps other chronic diseases.