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. It is also important to discover the molecular mechanism in the sperm, by which changes-in-gene-expression signals are passed to offspring. Use of representational difference analysis, bisulfite sequencing, and pyrosequencing has revealed hypomethylation in the spacer-promoter region of the ribosomal RNA gene in sperm from Cr(III)-treated males. Ribosomal RNA is implicated in both growth and cancer. In lung tissues of offspring, gene methylation is decreased, and ribosomal RNA increased. Further detailed characterization is in progress, as well as work with cultured mouse and human lung cells is allowing molecular manipulation and controlled endpoint analysis. New results implicate small nuclear RNAs in regulation of the rRNA gene in human lung cancer cells. Effects on offspring glucose, hormones, and body weights suggested that the Cr(III) effects could be related to energy metabolism. Therefore another protocol has been tried, involving limited diet restriction of fathers (24 hr fasting). Remarkably, this treatment 2 weeks before mating results in a highly significant reduction in average serum glucose in both male and female offspring. Alterations in offspring corticosterone, IGF1, and body weight are also noted though more variably. These results suggest that physiological transgenerational effects may be common and have implications for many widespread diseases in addition to cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005352-25
Application #
7592522
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2007
Total Cost
$463,355
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Schmidt, Adele L; Anderson, Lucy M (2006) Repetitive DNA elements as mediators of genomic change in response to environmental cues. Biol Rev Camb Philos Soc 81:531-43
Anderson, Lucy M; Riffle, Lisa; Wilson, Ralph et al. (2006) Preconceptional fasting of fathers alters serum glucose in offspring of mice. Nutrition 22:327-31
Anderson, Lucy M (2006) Environmental genotoxicants/carcinogens and childhood cancer: bridgeable gaps in scientific knowledge. Mutat Res 608:136-56
Shiao, Yih-Horng; Crawford, Erik B; Anderson, Lucy M et al. (2005) Allele-specific germ cell epimutation in the spacer promoter of the 45S ribosomal RNA gene after Cr(III) exposure. Toxicol Appl Pharmacol 205:290-6
Anderson, Lucy M (2004) Introduction and overview. Perinatal carcinogenesis: growing a node for epidemiology, risk management, and animal studies. Toxicol Appl Pharmacol 199:85-90
Souliotis, Vassilis L; Sfikakis, Petros P; Anderson, Lucy M et al. (2004) Intra- and intercellular variations in the repair efficiency of O6-methylguanine, and their contribution to kinetic complexity. Mutat Res 568:155-70
Cheng, R Y S; Birely, L A; Lum, N L et al. (2004) Expressions of hepatic genes, especially IGF-binding protein-1, correlating with serum corticosterone in microarray analysis. J Mol Endocrinol 32:257-78
Anderson, Lucy M (2004) Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination. Toxicol Appl Pharmacol 199:162-74
Cheng, Robert Y-S; Hockman, Tyler; Crawford, Erik et al. (2004) Epigenetic and gene expression changes related to transgenerational carcinogenesis. Mol Carcinog 40:1-11
Cisneros, Francisco Javier; Wilson, Ralph; Travlos, Gregory et al. (2003) Susceptibility to postnatal growth retardation induced by 5-AZA-2'-deoxycytidine in utero: gender specificity and correlation with reduced insulin-like growth factor 1. Life Sci 72:2887-94

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