Alteration in diethylstilbestrol-induced mutagenicity and cell transformation by exogenous metabolic activation

Tsutsui, Takeki; Suzuki, Nobuko; Maizumi, Heiji; Ja, McLachlan; Jc, Barrett

doi:10.1093/carcin/7.9.1415

Cited by 25 publications

(11 citation statements)

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“…However, treatment of SHE cells with DES in the presence of an exogenous metabolic activation system enhances the frequency of morphological transformation of the cells. Furthermore, this treatment elicits UDS and gene mutations in the cells at the Na+/K+-ATPase locus (33). Thus, we have proposed two potential mechanisms for estrogen-induced cell transformation; in one the target of the estrogen is not DNA but rather microtubule disruption and the other is associated with DNA damage (33).…”

Section: Genotoxicitymentioning

confidence: 99%

“…Although DES is not genotoxic in many assays, in certain studies DES has been found to induce UDS (21,(70)(71)(72), sister chromatid exchanges (73)(74)(75), chromosome aberrations (76,77) and gene mutations (33,78). The positive studies of DNA damage by DES use either cultured mammalian cells with exogenous metabolic activation or cells with possible endogenous activation capacity for DES.…”

Section: Genotoxicitymentioning

confidence: 99%

“…Therefore, we directly compared the cell transforming activity and genotoxicity of DES in the same cells with and without exogenous metabolic activation. When SHE cells are treated in the absence of a rat liver PMSmetabolic activation system, DES fails to induce DNA damage in SHE cells at doses that induce cell transformation (7,19,20,21,33). However, treatment of SHE cells with DES in the presence of an exogenous metabolic activation system enhances the frequency of morphological transformation of the cells.…”

Section: Genotoxicitymentioning

confidence: 99%

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Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals.

Tsutsui

Barrett

1997

Environ Health Perspect

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Estrogen use has been associated with an increased risk for breast cancer and endometrial cancers in women (1-4). Various natural and synthetic estrogens also induce mammary, pituitary, cervical, uterine, and renal tumors in rodents (4-5). Diethylstilbestrol (DES), a synthetic estrogen, is well known to be carcinogenic to humans (6). The cellular and molecular mechanism(s) whereby estrogen-induced neoplastic events occur have not been fully elucidated, but there is strong evidence that estrogens are epigenetic carcinogens, acting via a promoting effect related to cellular proliferation, mediated through the estrogen receptor (7-15). However, it has been shown that estrogenic activity is not sufficient to explain the carcinogenic activity in vivo and in vitro under certain experimental conditions. Another mechanism, related to mutagenic changes, has been suggested in studies of estrogen-induced carcinogenesis (16)(17)(18)(19)(20)(21)(22)(23)(24) into the cellular and molecular mechanisms of carcinogenesis, which is difficult in whole-animal or human systems. We have used Syrian hamster embryo (SHE) fibroblast cell cultures as a model system to study the ability of estrogens to directly transform cells. Morphological and Neoplastic Transformation in Vitro by Estrogens and Estrogenlike ChemicalsMorphological and neoplastic transformation of SHE cells is induced by DES, 17,-estradiol (E2) and other estrogens. We observed that DES and E2 induce transformation of hamster cells that is indistinguishable from that induced by other chemical carcinogens such as benzo [a]pyrene (19,25). Sarcomas are also induced in Syrian hamsters in vivo following subcutaneous injection of DES (26). SHE cells do not express measurable levels of estrogen receptor and estrogen treatment is not mitogenic to the cells (27). Thus, estrogenic activity of the compounds can be excluded in this in vitro assay. The cells do, however, have the ability to metabolize estrogens (28,29), and the role of metabolic activation in the carcinogenesis activity of estrogens in this model is under investigation as discussed later.The role of mutagenesis in the neoplastic transformation of SHE cells by estrogens has been studied extensively. We have demonstrated that treatment of SHE cells with DES or E2 induces cell transformation without measurable gene mutations, unscheduled DNA synthesis (UDS) or structural chromosome aberrations (19,20,23

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Section: Genotoxicitymentioning

confidence: 99%

Section: Genotoxicitymentioning

confidence: 99%

Section: Genotoxicitymentioning

confidence: 99%

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Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals.

Tsutsui

Barrett

1997

Environ Health Perspect

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“…If there was displacement, they were scored as breaks. In some experiments, the chromosome aberration assay was carried out in the presence of exogenous metabolic activation with rat liver post-mitochondrial supernatant (PMS), as described previously (4). Cells (5´10…”

mentioning

confidence: 99%

“…This treatment condition is optimal for inducing gene mutations in SHE cells treated with indirectly acting chemical carcinogens (4). Cells were washed twice with 5 ml PBS(-) and incubated with fresh medium for 18 h followed by chromosome preparations.…”

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confidence: 99%

Ability of Fourteen Chemical Agents Used in Dental Practice to Induce Chromosome Aberrations in Syrian Hamster Embryo Cells

et al. 2005

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Abstract. To assess the genotoxicity of 14 chemical agents used in dental practice, the ability of these agents to induce chromosome aberrations was examined using Syrian hamster embryo (SHE) cells. Statistically significant increases in the frequencies of chromosome aberrations were induced in SHE cells treated with 7 of 10 chemical agents used as endodontic medicaments, that is, carbol camphor, m-cresol, eugenol, guaiacol, zinc oxide, hydrogen peroxide, and formaldehyde. The other 3 chemical agents, that is, thymol, glutaraldehyde, and iodoform, did not increase the levels of chromosome aberrations. Of the 4 chemical agents that are used as an antiseptic on the oral mucosa, chromosome aberrations were induced by iodine, but not by the other 3 antiseptics, benzalkonium chloride, benzethonium chloride, and chlorhexidine. Among the 6 chemical agents exhibiting a negative response in the assay, only thymol induced chromosome aberrations in the presence of exogenous metabolic activation. Our results indicate that chemical agents having a positive response in the present study are potentially genotoxic to mammalian cells and need to be studied further in detail.

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17?-Estradiol, diethylstilbestrol, tamoxifen, toremifene and ICI 164,384 induce morphological transformation and aneuploidy in cultured Syrian hamster embryo cells

et al. 1997

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Many estrogenic chemicals are carcinogenic in different species. Carcinogenicity of the synthetic estrogen diethylstilbestrol (DES) is demonstrated in humans and in rodents (IARC, 1979). The natural steroidal estrogen 17b-estradiol (E 2 ) also exhibits carcinogenic activity in a number of experimental animals (IARC, 1979). The mechanism of carcinogenesis by estrogens has not been fully elucidated, but strong evidence exists to support the hypothesis that estrogens are epigenetic carcinogens acting via a promoting effect related to cellular proliferation mediated by the estrogen receptor (ER) (Sheehan et al., 1982). In contrast, experimental support for another mechanism, related to genotoxicity, has been provided in many reports for estrogen-induced carcinogenesis.DES has been shown to induce genotoxic effects in cultured mammalian cells with exogenous metabolic activation and in cells with possible endogenous activation capacity for DES (Tsutsui et al., 1986). We have studied the cell transforming activity and genotoxicity of DES and E 2 using Syrian hamster embryo (SHE) cells, which do not express measurable levels of the ER (Barrett et al., 1981;Tsutsui et al., 1983Tsutsui et al., , 1986Tsutsui et al., , 1987. The SHE cell transformation assay measures the induction of pre-neoplastic cells by scoring morphologically altered colonies of cells that form 7-8 days after exposure to chemical/physical carcinogens (Tsutsui et al., 1983). Treatment of SHE cells with DES or E 2 induces cellular transformation without measurable gene mutations, unscheduled DNA synthesis (UDS) or structural chromosomal aberrations (Barrett et al., 1981;Tsutsui et al., 1983Tsutsui et al., , 1987. Under the same conditions, both estrogens induce a specific type of genetic change, i.e., aneuploidy. Chromosome losses and gains are induced (Tsutsui et al., 1983(Tsutsui et al., , 1987, suggesting a non-disjunctional mechanism involved in the transforming activity. However, UDS and gene mutation at the Na 1 /K 1 ATPase locus are elicited when SHE cells are treated with DES in the presence of a rat liver postmitochondrial supernatant metabolic activation system. Enhancement of the transformation frequencies is accompanied with this treatment (Tsutsui et al., 1986). Thus, we have proposed 2 potential mechanisms for estrogen-induced cellular transformation: one does not involve direct DNA damage and the other one is associated with DNA damage. Cellular DNA damage induced by chemicals can be examined by detection of DNA adduct formation through covalent modification of DNA. Liehr et al. (1986) demonstrated the presence of covalent DNA adducts in pre-malignant lesions in the kidneys of Syrian hamsters treated chronically with estrogens using a 32 P-postlabeling assay. In addition, exposure of SHE cells to DES and E 2 leads to covalent DNA adduct formation, corresponding to induction of cellular transformation (Hayashi et al., 1996).The triphenylethylene non-steroidal tamoxifen (TAM), which is a structural analogue of DES (Fig. 1), exerts anti-estro...

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Alteration in diethylstilbestrol-induced mutagenicity and cell transformation by exogenous metabolic activation

Cited by 25 publications

References 0 publications

Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals.

Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals.

Ability of Fourteen Chemical Agents Used in Dental Practice to Induce Chromosome Aberrations in Syrian Hamster Embryo Cells

17?-Estradiol, diethylstilbestrol, tamoxifen, toremifene and ICI 164,384 induce morphological transformation and aneuploidy in cultured Syrian hamster embryo cells

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