Project 1 - In Utero Chemical Exposures, Immune Status, and Childhood Leukemia

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ABSTRACT Project 1 – In Utero Chemical Exposures, Immune Status, and Childhood Leukemia Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. There is compelling evidence that childhood ALL is often initiated in utero and ALL risk is affected by neonatal immune status. Children who developed ALL tend to have had more fulminant infections during the first year of life, despite having had less frequent exposure to common infections than controls. One plausible explanation for this apparent immune dysregulation in children who develop ALL is aberrant in utero programming of the immune system. There are several lines of evidence that support this hypothesis. First, we have observed that children who develop ALL later in life had lower levels of IL-10, an immunosuppressive cytokine, at birth. Second, both maternal infections during pregnancy and higher maternal immunoglobulin E (IgE) levels after birth are positively associated with ALL risk, suggesting a role for maternal modulation of fetal immune development in determining ALL risk. Finally, we have identified chemicals associated with increased risk of childhood ALL, some of which are potential modifiers of immune status, including polychlorinated biphenyls, polybrominated diphenyl ethers, polycyclic aromatic hydrocarbons, and tobacco smoke. The objective of this proposed project is to assess, for the first time, the interplay between in utero chemical exposures and the immune status of both the mother and the child in the development of childhood ALL. We hypothesize that specific in utero chemical exposures will impact maternal and neonatal immune status and the altered immune status increases the risk of childhood ALL. To test this hypothesis, we will leverage exceptional resources from two existing NIH-funded studies (through Core A): neonatal dried blood spots collected at birth (neonatal blood spots) from the California Childhood Leukemia Study (CCLS), a population-based case-control study, and paired samples of neonatal blood spots and second trimester maternal serum from the California Mother-Child Birth Cohort. In both populations, we will (1) characterize immune status by measuring immunomodulatory cytokines in biospecimens, (2) examine whether in utero chemical exposures (identified in Project 2) influence immune status, and (3) assess the relation of in utero chemical exposures to the risk of childhood ALL, while accounting for immune status. In the CCLS population, home dust measurements and self-reported chemical exposures will be used to further characterize in utero chemical exposures, and data on maternal infections during pregnancy will be used to help characterize maternal immune status. An engineered mouse model of childhood ALL will be used to elucidate mechanisms by which in utero chemical exposures and maternal/neonatal immune status interact to initiate ALL (through Core C). In addition, data on maternal/neonatal immune status will be incorporated in the analysis of DNA methylation (Project 3). Our proposed project will fill important knowledge gaps in the etiology of childhood ALL, and further the understanding of immunomodulatory effects of in utero chemical exposures.