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Epigenetic and gene expression changes related to transgenerational carcinogenesis
Robert Y-S Cheng1, Tyler Hockman, Erik Crawford
1Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Molecular Carcinogenesis
|April 27, 2004
Summary
Chromium exposure in fathers can epigenetically alter cancer risk in offspring. This transgenerational effect involves changes in sperm DNA methylation and offspring gene expression, impacting growth and potentially tumor suppression.
Area of Science:
- Environmental toxicology
- Epigenetics
- Transgenerational inheritance
Background:
- Transgenerational carcinogenesis describes cancer risk transmission to offspring from parental exposure to carcinogens.
- Epigenetic mechanisms, including hormonal and gene expression alterations, are hypothesized to mediate this process.
Purpose of the Study:
- To investigate the epigenetic and hormonal mechanisms of transgenerational carcinogenesis using a mouse model.
- To determine if paternal exposure to chromium(III) chloride affects offspring cancer risk and associated molecular changes.
Main Methods:
- Mice (NIH Swiss) fathers were exposed to chromium(III) chloride before mating.
- Sperm DNA methylation was analyzed using Methylation-Sensitive Restriction Enzyme Analysis (MS-RDA) and bisulfite sequencing.
- Offspring growth, serum triiodothyronine (T3) levels, and liver gene expression (via microarray) were assessed.
Main Results:
- Paternal chromium exposure led to increased undermethylation of the 45S ribosomal RNA gene in sperm.
- Offspring of exposed fathers exhibited increased body weight and elevated serum T3 levels.
- Microarray analysis revealed significant correlations between serum T3 levels and the expression of 58 genes in offspring liver, some linked to growth and tumor suppression.
Conclusions:
- Paternal chromium exposure induces epigenetic changes in sperm, specifically rRNA gene undermethylation.
- Hormonal and gene expression alterations in offspring support an epigenetic mechanism for transgenerational carcinogenesis.
- These findings highlight the potential for environmental factors to influence cancer risk across generations.