Untargeted metabolomics in newborn dried blood spots: examples from pediatric leukemia and potential for Israel

The etiology of pediatric leukemia is largely unknown, but evidence for the requirement of multiple mutations in utero and long latency periods (up to 15 years) suggests that environmental factors play a causal role. Untargeted metabolomics is a powerful approach whereby measuring metabolites and chemicals in biological samples enables the investigation of global metabolome changes and measurement of exogenous exposures (i.e., exposomics) that can be linked with adverse health outcomes. Untargeted metabolomics of newborn dried blood spots (DBS) archived from the newborn screening program provide a means for retrospective investigation of in utero exposures as potential causal risk factors for rare pediatric diseases, including leukemia.

Using DBS from two nested case-control studies, we investigated untargeted metabolomics profiles at birth associated with subsequent development of leukemia in childhood. DBS from the CA Biobank were analyzed using Liquid Chromatography- High Resolution Mass Spectrometry (LC-HRMS). We identified four putative ceramides, a class of metabolites linked with cancer cell proliferation, as predictors of acute myeloid leukemia (AML) in females. Our analysis revealed sex-specific predictors of pediatric AML, suggesting different early life biology. In addition, folate pathway metabolites measured in newborn DBS were not predictive of pediatric acute lymphoblastic leukemia (ALL), indicating that late pregnancy may not be a sensitive time-period to possible protective effects of folate. While replication with larger numbers of subjects is required to validate the findings, these results point to the potential of this valuable bioarchive for etiological discovery in pediatric disease. Opportunities for similar studies in Israel will be discussed.