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Target organ-specific covalent DNA damage preceding diethylstilbestrol-induced carcinogenesis
Abstract:
The synthetic estrogen diethylstilbestrol (DES), a known human carcinogen, induces renal carcinoma in male Syrian hamsters within 6 months after s.c. implantation. Tumor formation could be evoked by its hormonal properties or by a reactive genotoxic metabolite binding to DNA, but previous attempts to detect adducts have failed. In the present study, kidney DNA of male Syrian hamsters, treated with s.c. DES implants to induce renal carcinoma, was analyzed for the presence of DES-induced adducts using 32P-postlabeling assay. Covalently-modified DNA nucleotides were detected in the kidneys after chronic DES treatment, but not in kidneys of untreated hamsters, or in liver or tumor tissue of DES-treated animals. This report demonstrates for the first time the ability of an estrogen to give rise to covalent DNA modification in vivo specifically in the target organ of carcinogenesis. DES-induced covalent DNA adducts are taken as evidence for tumor initiation by DES via damage to cellular macromolecules, in addition to tumor-promotional effects described previously.
Insights
Diethylstilbestrol (DES), a synthetic estrogen and carcinogen, forms DNA adducts in hamster kidneys, initiating renal carcinoma. This study confirms estrogen-induced DNA damage in vivo as a key step in cancer development.
Area of Science:
- Endocrinology
- Toxicology
- Molecular Biology
Background:
- Synthetic estrogens like diethylstilbestrol (DES) are known human carcinogens.
- DES induces renal carcinoma in male Syrian hamsters.
- The mechanism of DES-induced carcinogenesis, whether hormonal or genotoxic, remained unclear due to failed adduct detection.
Purpose of the Study:
- To investigate the presence of DES-induced DNA adducts in the kidneys of male Syrian hamsters.
- To determine if DES directly damages DNA in the target organ of carcinogenesis.
- To elucidate the role of DNA modification in DES-induced renal carcinoma.
Main Methods:
- Male Syrian hamsters were treated with subcutaneous implants of DES.
- Kidney DNA was analyzed for covalent modifications using the 32P-postlabeling assay.
- DNA from liver and tumor tissues, as well as kidneys of untreated hamsters, served as controls.
Main Results:
- Covalently-modified DNA nucleotides were detected in the kidneys of hamsters chronically treated with DES.
- No DES-induced DNA adducts were found in the kidneys of untreated hamsters.
- Analysis revealed no adducts in the liver or tumor tissue of DES-treated animals, indicating organ specificity.
Conclusions:
- This study provides the first in vivo evidence of estrogen-induced covalent DNA modification.
- DES directly damages DNA in the target organ, the kidney, during carcinogenesis.
- DES-induced DNA adducts support a genotoxic mechanism contributing to tumor initiation, alongside previously known promotional effects.