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Transplacental genotoxicity of diethylstilbestrol
1Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77550-2782.
Abstract:
Diethylstilbestrol (DES) is a transplacental carcinogen in humans and in rodents. As part of an attempt to examine the mechanism of transplacental carcinogenesis, the transplacental genotoxity of this stilbene estrogen has been investigated. Pregnant hamsters received single injections of 200 mg/kg DES on the 10th day of gestation and were killed 5 or 24 h after treatment. The maternal organs were found to contain the same DES-DNA adduct patterns observed previously by 32P-postlabeling analysis in female hamsters. These adduct patterns, generated by the genotoxic metabolite diethylstilbestrol-4',4h'-quinone (DES Q), were also observed in fetal heart and kidney DNA. In fetal liver DNA, this modified nucleotide, generated by the quinone, was only the minor adduct. The major DNA adduct in this organ was not observed previously and may have been generated by an unknown DES metabolite. The data demonstrate that DES is a transplacentally active genotoxic agent. They also provide evidence for fetal metabolism of DES to DES Q and to other unknown genotoxic intermediates.
Insights
Diethylstilbestrol (DES) is a transplacental carcinogen. This study shows DES is genotoxic in fetal organs, indicating it crosses the placenta and damages fetal DNA, potentially causing cancer.
Area of Science:
- Toxicology
- Carcinogenesis
- Molecular Biology
Background:
- Diethylstilbestrol (DES) is a known human transplacental carcinogen.
- Understanding the genotoxic mechanisms of transplacental carcinogens is crucial for risk assessment.
- Previous studies have established DES's carcinogenic potential in various species.
Purpose of the Study:
- To investigate the transplacental genotoxicity of diethylstilbestrol (DES).
- To identify DNA adducts formed by DES and its metabolites in maternal and fetal tissues.
- To elucidate the role of fetal metabolism in DES-induced genotoxicity.
Main Methods:
- Pregnant hamsters were administered a single dose of DES (200 mg/kg) on day 10 of gestation.
- Maternal organs and fetal tissues (heart, kidney, liver) were collected 5 and 24 hours post-treatment.
- DNA was extracted and analyzed for adducts using 32P-postlabeling analysis.
Main Results:
- DES-DNA adduct patterns, attributed to the genotoxic metabolite diethylstilbestrol-4',4'-quinone (DES Q), were detected in maternal organs.
- Similar DES Q-related adducts were found in fetal heart and kidney DNA.
- A novel major DNA adduct was identified in fetal liver, suggesting the involvement of unknown DES metabolites.
Conclusions:
- Diethylstilbestrol (DES) is a transplacentally active genotoxic agent.
- Fetal tissues can metabolize DES to the genotoxic DES Q.
- Evidence suggests the existence of other, yet unidentified, genotoxic DES metabolites that can reach fetal organs.