Epigenetic and gene expression changes related to transgenerational carcinogenesis

Abstract

Transgenerational carcinogenesis refers to transmission of cancer risk to the untreated progeny of parents exposed to carcinogens before mating. Accumulated evidence suggests that the mechanism of this process is epigenetic, and might involve hormonal and gene expression changes in offspring. To begin to test this hypothesis, we utilized a mouse model (NIH Swiss) in which exposure of fathers to Cr(III) chloride 2 wk before mating can alter incidence of neoplastic and nonneoplastic changes in offspring tissues. Utilizing a MS-RDA approach, we found that the sperm of these fathers had a significantly higher percentage of undermethylated copies of the 45S ribosomal RNA gene (rRNA); this finding was confirmed by bisulfite sequencing. Because gene methylation is a known mechanism of expression control in germ cells, and ribosomal RNA levels have been linked to cancer, these findings are consistent with the hypothesis. Secondly, we observed that offspring of Cr(III)-treated fathers were significantly heavier than controls, and had higher levels of serum T3. Possible effects of T3 levels on gene expression in the offspring were examined by microarray analysis of cDNAs from liver. A total of 58 genes, including 25 named genes, had expression ratios that correlated significantly with serum T3 ratios at P </= 0.001. Some of these genes have potential roles in growth and/or tumor suppression. These results also support the hypothesis of an epigenetic and/or gene expression-based mechanism for transgenerational carcinogenesis. Published 2004 Wiley-Liss, Inc.

Chromium Cross-Links Histone Deacetylase 1-DNA Methyltransferase 1 Complexes to Chromatin, Inhibiting Histone-Remodeling Marks Critical for Transcriptional Activation

“…These observations raise the possibility that chromium exposure during development may also modify developmental imprinting patterns and be related to transgenerational carcinogenesis. Consistent with this prediction, paternal exposure to chromium prior to mating was found to alter the incidence of neoplastic and nonneoplastic changes in mouse tissues of the offspring (6). In this context, regulation of the p16 ink4a tumor suppressor gene appears to be a major target of chromium toxicity.…”

Prospects for Epigenetic Epidemiology

“…Chromium exposure in male mice, for example, causes hypomethylation of sperm genomic DNA and is associated with increasing risk of tumors and other abnormalities in progeny (131,132).…”

Epigenetic reprogramming and imprinting in origins of disease

“…Heavy metals such as chromium (Cr), cadmium (Cd), arsenic (As), lead (Pb), and nickel (Ni) have been reported to exert epigenetic effects on the genome. Paternal exposure to Cr(III) was shown to modify the epigenome/genome and to induce transgenerational carcinogenesis [64]. Paternal exposure to Cr(III) increases tumor risk in offspring.…”