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Relative carcinogenic activity of various synthetic and natural estrogens in the Syrian hamster kidney
Abstract:
Both synthetic and natural estrogens have been studied for their ability to induce renal carcinomas in castrated male hamsters after 9.0 months of treatment. Tumor foci were detected in frozen serial sections stained histochemically for estrase activity. Both diethylstilbestrol (DES) and 17 beta-estradiol had equal ability (100%) to induce renal tumors [approximately 20.5 +/- 3 (S.E.) tumor foci] in these animals. Hexestrol induced the same incidence and number of renal carcinoma foci as DES or 17 beta-estradiol. However, alpha -dienestrol and DES 3,4-oxide showed an 86 to 88% incidence of renal tumors in hamsters (approximately 10.8 +/- 3). When equilin and d-equilenin, components of therapeutic conjugated estrogens, were tested, only equilin had a 76% incidence of renal tumor foci (5.5 +/- 0.9). The ability of these stilbene and steroidal estrogens to compete for renal tumor estrogen receptor generally correlated well with their ability to cause renal tumorigenesis in the hamster with one notable exception. Although ethinyl estradiol competed as well as did DES or 17 beta-estradiol for estrogen receptor, had similar ability to induce renal progesterone receptor, and led to similar high serum prolactin levels as either DES or 17 beta-estradiol, it had only weak carcinogenic activity (21%) in the hamster kidney (0.6 +/- 0.5 foci). These data represent the first detailed analysis of the relative carcinogenic activity of different estrogens within a given tumor-inducing system, and based on the carcinogenicity data of hexestrol and alpha-dienestrol presented herein, they suggest that epoxidation of the olefinic double bond and the p-quinone metabolite of DES probably are not involved significantly in its carcinogenic activity. Moreover, the poor carcinogenic activity of ethinyl estradiol in this system, despite strong estrogenicity, suggests that estronic activity alone may not be sufficient to effect renal tumorigenesis in the hamster.
Insights
Synthetic and natural estrogens were tested for kidney cancer induction in hamsters. Diethylstilbestrol (DES) and 17 beta-estradiol were potent carcinogens, while ethinyl estradiol showed weak activity despite strong estrogenicity.
Area of Science:
- Endocrinology
- Carcinogenesis Research
- Toxicology
Background:
- Estrogens are known to influence various physiological processes, including potential carcinogenic effects.
- Previous studies have indicated a link between estrogen exposure and renal tumors in certain animal models.
- Understanding the dose-response and structural activity relationships of different estrogens is crucial for risk assessment.
Purpose of the Study:
- To compare the relative carcinogenic activity of various synthetic and natural estrogens in inducing renal tumors in castrated male hamsters.
- To investigate the correlation between estrogen receptor binding affinity and tumorigenic potential.
- To explore the role of specific metabolic pathways and estrogenic potency in renal carcinogenesis.
Main Methods:
- Castrated male hamsters were treated with different estrogens for 9 months.
- Tumor incidence and foci were quantified in kidney sections.
- Histochemical staining for esterase activity was used to detect tumor foci.
- Estrogen receptor binding competition assays were performed.
Main Results:
- Diethylstilbestrol (DES), 17 beta-estradiol, and hexestrol induced renal tumors with 100% incidence.
- Alpha-dienestrol and DES 3,4-oxide showed 86-88% incidence.
- Equilin induced a 76% incidence, while d-equilenin showed no significant activity.
- Ethinyl estradiol exhibited weak carcinogenic activity (21%) despite potent estrogenicity and high prolactin induction.
Conclusions:
- Estrogenic activity alone may not be sufficient for renal tumorigenesis in hamsters.
- The carcinogenic activity of estrogens in this model generally correlates with estrogen receptor binding, with notable exceptions.
- Metabolic pathways like epoxidation may not be critical for DES-induced renal carcinogenesis.