Analysis of Genotoxic Biomarkers in Children Associated with a Pediatric Cancer Cluster and Exposure to Two Superfund SitesEPA Grant Number: CR830757
Title: Analysis of Genotoxic Biomarkers in Children Associated with a Pediatric Cancer Cluster and Exposure to Two Superfund Sites
Investigators: Finette, Barry A.
Institution: University of Vermont
EPA Project Officer: Hahn, Intaek
Project Period: March 1, 2003 through February 28, 2006 (Extended to December 31, 2007)
Project Amount: $775,141
RFA: Children's Vulnerability to Toxic Substances in the Environment (2002) RFA Text | Recipients Lists
Research Category: Children's Health , Health Effects , Human Health , Health
The objective of this study is to evaluate the utility of specific biomarkers of effect and susceptibility for studying cancer risk in a pediatric population following genotoxic exposures. We will determine if children from an exposed population with elevated cancer incidence have an increase in chromosome aberrations as well as the following changes in HPRT mutational spectrum: 1) an increase in frameshift mutations reflective of exposure to anthraquinone-based dyes and styrene-acrylonitrile trimers; 2) an increase in point mutations reflective of exposure to benzidine-based dyes, epichlorohydrin and trichloropropane; and 3) an increase in V(D)J recombinase mediated deletions reflective of exposure to aromatic hydrocarbons. We will also determine if specific DNA polymorphisms of 11 carcinogen-metabolizing enzymes are associated with increased susceptibility to genotoxic exposure.
We will measure biomarkers of effect and susceptibility in exposed siblings of children in a CDC defined pediatric cancer cluster that has been linked to transplacental and childhood exposure to contaminated groundwater from two EPA designated superfund sites in Dover Township, NJ. The exposed siblings are the focus of the study rather than the children with cancer because of the genotoxic effects of cancer treatment. However, biomarkers of susceptibility will also be measured in children with cancer. Biomarkers of effect (chromosomal aberrations and HPRT mutations) in the exposed siblings will be compared to measurements in unexposed children from neighboring communities. Biomarkers of susceptibility (DNA polymorphisms for carcinogen metabolizing enzymes) in the exposed siblings and unexposed children will be compared to children with cancer to determine if the latter have a higher prevalence of specific metabolic genotypes. In addition, the relationships between biomarkers of effect and susceptibility in exposed siblings and unexposed children will be examined to see if the effects of exposure are modified by certain metabolic polymorphisms. Exposures in all subjects will be evaluated from their residential and personal histories, using a computer model developed by the ATSDR to estimate exposure to different water sources over time.
This study will provide important information about the utility of specific biomarkers for studying the genetic effects of transplacental and childhood exposure to genotoxic agents. If their validity is established, the biomarkers will be useful tools for assessing cancer risk in potentially exposed populations of children before an increase in incidence becomes evident. In addition, the study will help elucidate mechanisms of carcinogenesis in children and thus assist in the interpretation of results from the current epidemiologic study of childhood cancers in Dover Township.