Fetal Origins of Testicular Cancer: A Metabolomics Study in Newborns

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PROJECT SUMMARY/ABSTRACT Testicular cancer, mainly comprised of testicular germ cell tumors (TGCT), is the most common solid tumor among adolescent and young adult males. Its incidence has increased dramatically during the past 40 years worldwide and in the US. Compared to other racial/ethnic groups, Latinos experience the highest increase in both incidence and mortality rates since 2000, leading to major health disparities. In addition, the disease burden is high in terms of serious life-long treatment-related complications in cancer survivors, and years of potential life lost in this young population. As a result, etiologic and prevention research of TGCT is of high public health importance. The rapid increase in TGCT incidence suggests that environment plays an important etiology role, yet no environmental risk factors to date have been identified. Some reports have suggested that exposure to endocrine disrupting chemicals during pregnancy may be associated with future risk of TGCT, but no human studies have directly tested this hypothesis. TGCT is believed to have fetal origin and to develop from an initiating event occurring in utero, resulting in a precursor lesion that progresses to TGCT in nearly all cases; the difficulty in obtaining prospectively collected (pre-diagnosis) biological specimens from this critical period of development (prenatal) has posed a major limitation to the identification of environmental risk factors. The field of “exposomics” studies all relevant chemical exposures; metabolomics platforms estimate the “internal” environment of an individual that may identify both exogenous exposures involved in disease development. By leveraging newborn dried blood spots archived by the state of California on all infants born in the state, we will conduct a detailed “exposomic” analysis of fetal life that could identify environmental triggers in TGCT etiology. Using an untargeted analysis which measures thousands of exogenous and endogenous metabolites simultaneously permits us to make inference on fetal exposure and in utero metabolism and biologic response. Additionally, we will apply novel statistical methods that simultaneously examine thousands of biochemical signatures. Using a semi- targeted approach, we will also test the hypothesis that birth levels of phthalates, an endocrine disruptor associated with male genital anomalies, is associated with TGCT risk. Our proposed study is novel in that it overcomes conceptual and methodological challenges that have hindered previous studies of the fetal origin of TGCT (especially access to blood specimens collected at birth to characterize the fetal/neonatal periods); utilizes untargeted and semi-targeted approaches to identify a large number relevant biochemical signatures and to test current hypotheses in TGCT environmental epidemiology; and uses novel statistical methods to examine two and three way interactions without the need for large sample sizes. Our large and ethnically diverse California- based study population will provide the opportunity to fill important knowledge gaps about the factors contributing to TGCT.