Epigenetic and gene expression changes related to transgenerational carcinogenesis.
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.
Cheng
Robert Y-S
RY
Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Hockman
Tyler
T
Crawford
Erik
E
Anderson
Lucy M
LM
Shiao
Yih-Horng
YH
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D017252:CD3 Complex / Q000097:blood; D002712:Chlorides / Q000633:toxicity*; D017608:Chromium Compounds / Q000633:toxicity*; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D019175:DNA Methylation; D004275:DNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D018812:Paternal Exposure; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D013094:Spermatozoa / Q000187:drug effects
D015415:Biomarkers; D017252:CD3 Complex; D002712:Chlorides; D017608:Chromium Compounds; D004275:DNA, Ribosomal; D012335:RNA, Ribosomal; C088179:RNA, ribosomal, 45S; D004247:DNA; C017133:chromous chloride