Prenatal Exposures &Procarcinogenic Mutations

DESCRIPTION (provided by applicant): Molecular and traditional epidemiology studies have indicated a possible relationship between in utero environmental exposures and increased risk for childhood cancers, especially acute leukemias. We propose to evaluate pre- natal environmental exposures that may increase the risk of childhood ALL. We propose to measure chromosomal aberrations, a validated biomarker of cancer risk, in a subset of newborns from the Columbia Center for Children's Environmental Health (CCCEH) Prospective Cohort Study. The parent study population is comprised of non-smoking mothers and newborns residing in low-income, minority neighborhoods in New York City, who are subject to varying levels of environmental exposures including polycyclic aromatic hydrocarbons (PAH) and organophosphate pesticides such as chlorpyrifos. Prenatal exposures have been assessed by questionnaires, air monitoring, and biomarkers. In a pilot study, we have examined the frequency and range of chromosome aberrations in cord blood in a small subset of the CCCEH population using fluorescence in situ hybridization (FISH) with whole chromosome painting probes for chromosomes 1-6. After adjustment for whole genome equivalents, we have found that the frequencies of stable and total chromosomal aberrations are significantly associated with exposure to PAH and chlorpyrifos, measured in air samples obtained by personal air monitoring during the third trimester of pregnancy. Contrary to expectation, the number of aberrations observed per painted chromosome in this study population is not proportional to DNA content, suggesting that certain chromosomes are more sensitive to certain chemical agents. In addition, our pilot data suggest that presence of certain metabolizing enzyme polymorphisms (GSTPI/CYPlal) in infants and their mothers predicts response to prenatal exposures in terms of increased chromosomal aberrations in the infants' cord blood. Other studies indicate that polymorphisms in the PON1 gene involved in the detoxification of organophosphates are also likely to affect the development of chromosomal aberrations. Infant DNA repair capacity (XPD/XRCC1) probably also plays a role in the persistence of chromosomal damage. We therefore wish to explore the role of fetal and maternal genotypes on the mediation of environmental exposures and the development of chromosomal aberrations in the fetus. We propose to expand our pilot study to include a total of 300 newborns from the CCCEH cohort in order to better examine the relationship between exposures to PAH and household pesticides and levels of chromosomal aberrations. We have previously shown that chromosomal translocations characteristic of pediatric leukemia often arise pre-natally, probably as initiating events. In order to better understand a possible link to the first step in leukemogenesis, we will examine samples obtained at delivery from 300 cohort members and an additional 100 samples from a subset of the same children at age two, for the presence of chromosomal aberrations. As a pilot initiative, we will also examine the fusion product, TEL-AMLI. We have previously found TEL-AML1, which is thought to be a necessary but not sufficient step for the development of childhood ALL, to be present in healthy newborns at a frequency 100- fold that of the incidence of ALL. The origin of these initial chromosomal translocations is not known but appears to be linked to prenatal environmental exposures. Chromosomal abnormalities, both those involving specific leukemogenic translocations and those in other areas of the genome, may offer useful information on the etiologic agents involved in leukemogenesis and/or the chromosomes susceptible to these toxicants. Moreover, the utility of chromosomal aberrations to measure genetic damage incurred in utero from PAH and pesticide exposures has not been assessed in a minority population with disproportionately high exposure to these pollutants. Increases in chromosomal aberrations are an established risk marker for cancer, particularly hematological cancers. Thus they may be able to provide information on cancer risk in relationship to PAH and pesticides. Thus far, the link between these exposures and cancer risk has not been adequately studied in more susceptible populations such as fetuses or children exposed to high levels of common urban contaminants. Our proposed study also offers a unique opportunity to explore variations in susceptibility to chromosomal aberrations. Such data can help inform us of the full range of carcinogenic risk from environmental exposures and thus contribute to the formation of policies that will protect populations at greatest risk. Thus, the ultimate goal of this research is to contribute to the prevention of future childhood ALL.