Persistent Organochlorines and Testicular Cancer Risk

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DESCRIPTION: The incidence of testicular germ cell carcinoma (TGCC), the most common malignancy developing in young men, has increased several-fold since the 1950s. Experimental and observational studies in animal systems have raised concern that the increasing rates are due in part to population-wide, persistent exposure to endocrine disrupting compounds from industrial and agricultural applications. Whether human exposure to such chemicals is associated with TGCC risk has not been directly studied. We propose to determine whether the risk of TGCC is related to serum levels of persistent organochlorines, focusing on p,p'-DDE, polychlorinated biphenyls (PCBs), and other compounds (e.g., dieldrin, hexachlorocyclohexanes, hexachlorobenzene). We also will examine whether the risk of TGCC associated with these compounds is modified by genetic susceptibility to mechanisms through which these compounds may alter TGCC risk. For example, we will determine whether TGCC risk is related to interactions between 1) elevated serum p,p'-DDE and polyglutamine repeat tract polymorphisms in the androgen receptor (AR) gene, and 2) elevated serum PCB levels and polymorphisms in oxidative stress defense enzyme genes. To address these aims, we will conduct an ancillary investigation to the Male Androgen Research Study (MARS), a recently-initiated, NCI-funded, population-based case-control study of molecular genetic risk factors for TGCC. MARS funding includes standard population-based case and control ascertainment and recruitment, a detailed in-person interview, blood draw, and molecular genetic analyses of polymorphisms in androgen synthesis, metabolism, and signaling genes (including AR). The ancillary study will include approximately 250 cases of TGCC and 750 controls recruited as part of MARS. Funding for the ancillary study will provide for 1) a rapid case ascertainment and recruitment system to minimize effects of chemotherapy on serum measures of organochlorine residues among TGCC patients; 2) assay of organochlorine pesticides and PCBs by high resolution gas chromatography/isotope dilution high resolution mass spectometry; and 3) assays for common polymorphisms in genes involved in oxidative stress defense systems (manganese superoxide dismutase, glutathione S-transferases M1, M3, T1, and P1). There will be adequate statistical power to detect relatively weak overall associations, as well as less than 3-fold interaction effects. The results should add significant new information to our understanding of the role of environmental contaminants to the pathogenesis of TGCC.