Effect of aflatoxin B1-8,9-epoxide-DNA adducts on transcription of a supF gene fragment

Yu, Fu‐Li; Cahill, Jeanne M.; Lipinski, Leonora J.; Dipple, Anthony

doi:10.1016/s0304-3835(96)04423-0

Cited by 10 publications

(4 citation statements)

References 23 publications

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“…Additionally, it is believed that the semiquinone and quinone forms of estrogens can covalently bind and form DNA adducts (42,43). The third hypothesis proposed by this laboratory two years ago (17) suggests that the aromatic A-ring of E1 and E2, like many of the well established chemical carcinogens, including aflatoxin B1 (25,(26)(27)(28)(29)(30)(31)(32)(33)44), and the polycyclic aromatic hydrocarbons (18)(19)(20)(21)(22)(23)(24), can be activated to epoxide and to bind DNA and to initiate carcinogenesis (see Figure 7).…”

Section: Discussionmentioning

confidence: 99%

“…Initiation involves the covalent binding of a chemical carcinogen to DNA which is believed to be the critical first step in carcinogenesis (18)(19)(20)(21)(22)(23)(24). From our previous studies on aflatoxin B1 (AFB1), a potent liver carcinogen (25), we have clearly demonstrated that 3 H-labeled AFB1 is able to bind DNA and to inhibit DNA-dependent RNA synthesis only after it is activated by the liver microsome P450 enzymes (26)(27)(28)(29)(30)(31), or by DMDO treatment (32,33). Furthermore, from correlation studies, it is possible to conclude that the inhibition of DNA-dependent RNA synthesis by AFB1 is a direct reflection of the binding of AFB1 to DNA (28,29).…”

Section: Introductionmentioning

confidence: 99%

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The transcriptional effects and DNA-binding specificities of 17beta- estradiol after dimethyldioxirane activation

Yu¹

1998

Carcinogenesis

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It was found recently that 17β-estradiol (E2) could be activated by the epoxide-forming oxidant dimethyldioxirane (DMDO) resulting in the inhibition of rat liver nuclear and nucleolar RNA synthesis in vitro (Carcinogenesis, 17, 1957(Carcinogenesis, 17, -1961(Carcinogenesis, 17, , 1996. To further study the mechanism of this inhibition, several synthetic DNAs with different base content and sequence were used to study the transcriptional effects and binding specificities of E2 after DMDO activation in vitro. The results show: (1) E2 after activation had a strong inhibitory effect on the template function of both A-T and G-C containing double-stranded DNAs, e.g. poly[d(A-T)], polydG·polydC and poly[d(I-C)], and only a weak inhibition on the single-stranded DNA template, polydC. The inhibition was dose-dependent, and only after DMDO activation. (2) 3 H-labeled E2, after DMDO activation, was able to bind DNAs containing both A-T and G-C bases. The order of the binding preference was: calf thymus DNA > poly[d(A-T)] > poly[d(G-C)]. (3)The covalent binding nature of E2 to DNA after activation was further confirmed by 32 P-post-labeling analysis using calf thymus DNA. (4) The absorption spectrum of E2 changed, after DMDO treatment, from a peak around 280-290 nm to 260-270 nm with a shoulder appearing around 300-320 nm. These studies have not only confirmed our earlier observation that E2, after DMDO activation, can inhibit DNA-dependent RNA synthesis, but also provided new insights into the DNA-binding properties after activation. Additionally, since epoxidation is often required for the activation of chemical carcinogens to bind DNA, these studies lend further support to our proposed hypothesis that E2 epoxidation may play an initiation role in estrogen carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The transcriptional effects and DNA-binding specificities of 17beta- estradiol after dimethyldioxirane activation

Yu¹

1998

Carcinogenesis

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“…AFB 1 , on the other hand, manifests its toxicity-after undergoing biotransformation via the P 450 system-primarily via direct interactions with genetic material (specifically, G:C-rich regions of DNA). Ultimately, the bound AFB 1 causes alterations in DNA transcription (Yu et al, 1996), and, consequently, inhibition of protein synthesis. One key mechanism used to reduce the toxic potential of AFB 1 in a cell is activation of alpha class glutathione-S-transferase (Eaton and Gallagher, 1994).…”

Section: Discussionmentioning

confidence: 99%

Immunological status of the progeny of breeder hens kept on ochratoxin A (OTA)- and aflatoxin B₁(AFB₁)-contaminated feeds

Hassan

Khan

et al. 2012

Journal of Immunotoxicology

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This study aimed to evaluate the immunological status of progeny of hens kept on ochratoxin A (OTA)- and aflatoxin B(1) (AFB(1))-contaminated feed. For this purpose, White Leghorn (WL) layer breeder hens (40-weeks-of-age) were divided into six groups (A-F). Hens in Group A were fed a commercial layer ration while those in Groups B and C were kept on a diet amended with 3 and 5 mg OTA/Kg, respectively. Group D was fed a ration containing 5 mg AFB(1)/Kg, while hens in Groups E and F were kept on feed amended with OTA and AFB(1) each. All feedings were for 1, 2, or 3 weeks. Fertile eggs were set for hatching on a weekly basis to obtain progeny of each week separately. At 14 days-of-age, subsets of progeny were euthanized and the frequency of immunoglobulin(s)-bearing cells in their spleen and bursa of Fabricius assessed; at 16 days-of-age, other chicks in each set were utilized to determine their lymphoblastogenic responses against phytohemagglutinin (PHA-P). At 30 days-of-age, the final sub-set of chicks/group was euthanized and their peritoneal macrophages harvested for measurements of phagocytic potential and nitrite production. Relative weights of the bursa of Fabricius and of the spleen were significantly lower in the progeny of hens fed mycotoxin-contaminated diets for 14 and 21 days. The frequencies of IgA-, IgG-, and IgM-bearing cells were also significantly lower in the bursa of Fabricius and spleen of progeny chicks obtained from hens fed the OTA + AFB(1) mixed diet. Feeding contaminated diets to breeder hens also resulted in significantly lower responses to PHA-P. In addition, the percentages of peritoneal macrophages displaying phagocytosis of sheep red blood cells (SRBC), the number of SRBC/macrophage, and nitrite production were each significantly lower in cells from progeny chicks from OTA- and AFB(1)-fed hens. The findings of the present study indicated there were severe immunosuppressive effects in progeny chicks as a result of exposure of their parent hens to OTA and AFB(1) either alone or in combination. These studies provide emphasis for the need for mycotoxin regulation policy with respect to the ingredients used in poultry feed, since it is clear that feeding multi-mycotoxin-contaminated diets to breeder hens will almost certainly result in the hatching of manifestly unhealthy chicks.

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“…1). 13 Because epoxidation is required for the activation of many well‐known chemical carcinogens (e.g., benzo(a)pyrene, 7,12‐dimethylbenz(a)anthracene and aflatoxins), 14−23 we proposed that oestrogen epoxidation is the underlying mechanism for the initiation of breast cancer (Fig. 2).…”

Section: β‐Estradiol Epoxidation As the Underlying Mechanism Of Brementioning

confidence: 99%

17β‐Estradiol epoxidation as the molecular basis for breast cancer initiation and prevention

2002

Asia Pac J Clin Nutr

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Epidemiological and animal studies have indicated that 17beta-estradiol (E2) is involved in breast cancer; however, the mechanism is unclear. We found that E2 could be activated by epoxidation, resulting in its ability to inhibit nuclear DNA-dependent RNA synthesis, and to bind DNA, forming DNA adducts both in vitro and in vivo. Because epoxidation is required for the activation of many chemical carcinogens, including benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene and aflatoxins, we proposed previously that E2 epoxidation is the underlying mechanism for the initiation of breast cancer. The first part of this review is to present the experimental evidence obtained from this laboratory in support of this hypothesis. Based on these newly discovered insights on E2 epoxidation and its initiation role in breast cancer carcinogenesis, a method to screen chemopreventive agents against breast cancer has been developed. This constitutes the second part of the review. Two examples will be used to illustrate the utility of this screening technique. The effect of fat on breast cancer has been a longstanding but unresolved issue. Epidemiological studies provide conflicting results regarding the association of dietary fat and breast cancer. Because vegetable oils contain various amount of mono- and polyunsaturated fatty acids, they are potential antioxidants. Data are presented to show that commercial vegetable oils, independent of their mono- or polyunsaturated fatty acid content, are all able to prevent the formation of E2 epoxide, as measured by the loss of the ability of E2 to inhibit nuclear RNA synthesis in vitro. Tamoxifen (TAM), an anti-estrogen used for breast cancer treatment, has recently been found to have a strong breast cancer preventive effect. The mechanism for this is unknown. Using the same screening technique, we found that when incubated together with E2 for epoxidation, TAM was able to prevent the formation of E2 epoxide, as evidenced by both the loss of the ability of E2 to inhibit nuclear RNA synthesis and the reduced binding of [3H]-labelled E2 to nuclear DNA in a dose-dependent manner. These experimental results suggest that the breast cancer preventive effect of TAM is to prevent the formation of E2 epoxide through a competitive epoxidation mechanism with E2.

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Effect of aflatoxin B1-8,9-epoxide-DNA adducts on transcription of a supF gene fragment

Cited by 10 publications

References 23 publications

The transcriptional effects and DNA-binding specificities of 17beta- estradiol after dimethyldioxirane activation

The transcriptional effects and DNA-binding specificities of 17beta- estradiol after dimethyldioxirane activation

Immunological status of the progeny of breeder hens kept on ochratoxin A (OTA)- and aflatoxin B₁(AFB₁)-contaminated feeds

17β‐Estradiol epoxidation as the molecular basis for breast cancer initiation and prevention

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Effect of aflatoxin B1-8,9-epoxide-DNA adducts on transcription of a supF gene fragment

Cited by 10 publications

References 23 publications

The transcriptional effects and DNA-binding specificities of 17beta- estradiol after dimethyldioxirane activation

The transcriptional effects and DNA-binding specificities of 17beta- estradiol after dimethyldioxirane activation

Immunological status of the progeny of breeder hens kept on ochratoxin A (OTA)- and aflatoxin B1(AFB1)-contaminated feeds

17β‐Estradiol epoxidation as the molecular basis for breast cancer initiation and prevention

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Immunological status of the progeny of breeder hens kept on ochratoxin A (OTA)- and aflatoxin B₁(AFB₁)-contaminated feeds