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Symposium: Prenatal Exposure and Childhood Cancer

Prenatal exposures and childhood cancer.

Department of Environmental Health Sciences, Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, Department of Pediatrics & Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, Leukemia Research Laboratory, Institute for Cancer Research, London, United Kingdom, Department of Genetics & Development & Department of Pediatrics, Columbia University, New York, NY

Abstract

SY03-02

Many lines of evidence suggest a role for in utero environmental exposures in childhood cancer, especially in childhood acute lymphocytic leukemia (ALL). For example, the chromosomal rearrangement t(12;21), commonly seen in childhood ALL, is detectable in the neonatal blood spots (Guthrie cards) of the cases (6). Although data are conflicting, there is epidemiologic evidence that maternal exposure in pregnancy to pesticides, vehicle exhaust emissions, benzene, environmental tobacco smoke (ETS) as well as polymorphisms in children's genes that metabolize these xenobiotics (e.g., CYP1A1, GST-M1, -T1, -P1) are associated with childhood ALL (3;5)(4;8)(7). In addition to the NYC (NM) cohort, the populations were participants in a study of the effects of the World Trade Center (WTC) disaster, residents in Krakow, Poland, and residents in Tongliang, China. Mean adduct concentrations in both maternal and cord blood and the proportion of samples with detectable adducts increased across the populations [NM < WTC < Krakow < Tongliang], consistent with the trend in estimated ambient exposure to PAHs (p < 0.001). Despite the estimated 10-fold lower PAH dose to the fetus based on laboratory animal experiments, the adduct levels in the newborns were similar to or higher than in the mothers. This finding suggests that the fetus may be 10-fold more susceptible to DNA damage than the mother and that in utero exposure to PAHs may disproportionately increase carcinogenic risk. Heightened fetal susceptibility could result from higher rate of cell proliferation and differentiation, greater absorption or retention of xenobiotics, and/or less efficient detoxification, DNA repair, or apoptotic mechanisms. Chromosomal aberrations are a validated intermediate marker for increased risk for cancer. Using fluorescence in situ hybridization (FISH) with whole chromosome painting probes for chromosomes 1–6, we have measured chromosomal aberrations in a representative subset of 60 newborns of the CCCEH NYC cohort (2). The frequency of stable chromosomal aberrations was significantly associated with exposure to PAHs (p=< 0.01). Among the 22 newborns with available PAH-DNA adduct data, the relationship between adducts and chromosomal aberrations was not significant, possibly due to the small number of subjects with both biomarker measurements. ETS was not a significant predictor of aberrations. Preliminary analysis has shown that the number of aberrations observed per painted chromosome in this study population was not proportional to DNA content, suggesting that certain chromosomes may be more susceptible to breakage by certain chemical agents (1). These results show an association between prenatal exposure to airborne carcinogenic PAHs and chromosomal aberrations in cord blood, suggesting that such prenatal exposures have the potential to cause the type of cytogenetic damage that has been related to increased cancer risk in other populations. We are now analyzing chromosomal aberrations in larger numbers of newborns and children from the cohort. In addition, we are exploring mediation of the effect of environmental exposures on fetal chromosomal aberrations by fetal and maternal genotypes (e.g., GST-M1, -P1, -T1, CYP1A1, PON1). In addition to documenting the overall level of chromosomal damage in relation to in utero exposures, we are evaluating specific changes known to be directly pre-leukemogenic. The TEL-AML1 fusion product appears to be a necessary but not sufficient step for the development of childhood ALL (4;6)(6). The origin of these initial chromosomal translocations is not known but appears to be linked to prenatal exposures. We are currently analyzing cord blood samples from our cohort for TEL-AML1 in order to evaluate their possible relationship with prenatal exposures. These studies suggest that there is substantial transplacental exposure to carcinogens in the urban environment, that procarcinogenic genetic damage in the form of adducts and chromosomal aberrations results from prenatal exposures, and that the fetus is more susceptible to DNA damage than the mother. Further studies are ongoing to determine the persistence of chromosomal aberrations through early childhood and the relationship between prenatal exposures and specific pre-leukemogenic rearrangements in cord blood samples. Such molecular epidemiologic data can help inform us of the full range of carcinogenic risk from environmental exposures and thus contribute to the development of policies that will protect the young.