Perinatal exposures may lead to increased risk of childhood cancers, as well as those later in life. Preconceptional parental, transplacental, and/or neonatal exposures may be involved. Studies with animal models are utilized to increase understanding of underlying cellular and molecular mechanisms. A possible mechanism of paternal effects on childhood cancer is male-mediated transgenerational carcinogenesis. Exposure of male mice to chromium(III), an environmental/occupational metal, results in increased neoplasms and other lesions in the offspring. The nature of these changes suggested hormonal involvement. We have found that exposures of fathers to chromium(III) results in a highly significant 2-fold increase in average corticosterone in serum. Serum glucose was also significantly altered. Microarray analysis revealed hepatic insulin-like growth factor binding protein 1 (IGF BP1) as an important component of the effect. Hepatic IGF BP1 mRNA correlated strongly and positively with serum glucose in offspring of chromium-treated fathers, but negatively in offspring of control fathers. These results confirm striking effects of paternal exposures on hormonal and physiological parameters in offspring. Microarray was also utilized to study possible effects of chromium(III) on gene expression on Sertoli cells in culture; these cells might mediate the transgenerational effect in testis. Methods were developed for assessing the statistical significance of small changes in gene expression by microarray. The largest change was upregulation of the redox sensitive transcription factor, Bach 2. This can be pursued with in vivo studies.
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