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Estrogen-induced endogenous DNA adduction: possible mechanism of hormonal cancer
Abstract:
In animals and humans, estrogens are able to induce cancer in susceptible target organs, but the mechanism(s) of estrogen-induced carcinogenesis has not been elucidated. A well-known animal model is the development of renal carcinoma in estrogen-treated Syrian hamsters. Previous work demonstrated the presence of covalent DNA addition products (adducts) in premalignant kidneys of hamsters exposed to the synthetic estrogen, diethylstilbestrol, a known human carcinogen. In the present study, the natural hormone, 17 beta-estradiol, and several synthetic steroid and stilbene estrogens were examined by a 32P-postlabeling assay for their capacity to cause covalent DNA alterations in hamster kidney. Chronic exposure to each of the estrogens tested led to the gradual formation of five chromatographically distinct unusual nucleotides specifically in kidney DNA. Irrespective of the estrogen used, chromatograms exhibited identical mobilities of each of these adducts in seven different systems on PEI-cellulose anion-exchange TLC, in three different conditions on reversed-phase TLC, and in one system on silica gel partition TLC. Therefore, the DNA adducts observed did not contain moieties derived from the structurally diverse estrogens. It is concluded that each of the estrogens induced the binding of the same unknown endogenous compound (or compounds) to target tissue DNA. This novel property of estrogens is postulated to play a key role in hormone-induced malignancy.
Insights
Estrogens can cause cancer, but how is unknown. This study found that various estrogens bind the same unknown compound to hamster kidney DNA, suggesting a novel mechanism in hormone-induced cancer.
Area of Science:
- Endocrinology
- Carcinogenesis
- Molecular Biology
Background:
- Estrogens are known to induce cancer in susceptible organs in animals and humans.
- The precise mechanisms of estrogen-induced carcinogenesis remain largely unknown.
- Estrogen exposure leads to renal carcinoma in Syrian hamsters, a known animal model.
Purpose of the Study:
- To investigate the capacity of various natural and synthetic estrogens to induce covalent DNA alterations in hamster kidney.
- To elucidate the mechanism of estrogen-induced DNA damage and its potential role in carcinogenesis.
Main Methods:
- Utilized a 32P-postlabeling assay to detect DNA adducts in kidney DNA of estrogen-treated hamsters.
- Employed multiple chromatographic techniques (PEI-cellulose TLC, reversed-phase TLC, silica gel TLC) to characterize the DNA adducts.
- Examined both the natural hormone 17 beta-estradiol and several synthetic steroid and stilbene estrogens.
Main Results:
- Chronic exposure to all tested estrogens resulted in the formation of five distinct unusual nucleotides in kidney DNA.
- These DNA adducts exhibited identical chromatographic properties regardless of the specific estrogen used.
- Analysis indicated that the DNA adducts did not contain moieties derived from the tested estrogens, suggesting an endogenous origin.
Conclusions:
- Estrogens, irrespective of their structure, induce the binding of the same unknown endogenous compound(s) to DNA in target kidney tissue.
- This novel mechanism of estrogen action, involving the binding of an endogenous compound, is postulated to be a key factor in hormone-induced malignancy.
- The findings provide new insights into the molecular pathways of estrogen-mediated carcinogenesis.