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, and we have discovered alterations in serum glucose, corticosterone, IGF1, and the thyroid hormone T3. Microarray analysis has been utilized to identify hepatic genes whose expression changes correlate with differences in serum T3; these have included a number of genes related to growth and to tumor suppression. It is also important to discover the molecular mechanism in the sperm, by which changes-in-gene-expression signals are passed to offspring. A representational difference analysis technique has been utilized to screen for genes with altered methylation, a common mechanism for epigenetic control of gene expression. The gene for ribosomal RNA has been found to be hypomethylated in the sperm of Cr(III)-treated males, a result confirmed by bisulfite sequencing. Ribosomal RNA is implicated in both growth and cancer. Investigation of altered expression in offspring tissues is in progress. Once this molecular marker is confirmed, the hypothesis can be extended to human studies.
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