Showing papers on "7,12-Dimethylbenz[a]anthracene published in 2002"
Journal Article•
TL;DR: Results suggest that resveratrol suppresses DMBA-induced mammary carcinogenesis, which correlates with down-regulation of NF-kappaB, cyclooxygenase-2, and matrix metalloprotease-9 expression.
Abstract: We have reported recently that resveratrol ( trans -3,4′,5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, fruits, and root extracts of the weed Polygonum cuspidatum , is a potent inhibitor of nuclear factor (NF)-κB activation. Because NF-κB suppression has been linked with chemoprevention, this prompted us to investigate the chemopreventive potential of resveratrol by testing it against mammary carcinogenesis induced by 7,12-dimethylbenz( a )anthracene (DMBA) in female Sprague Dawley rats. Dietary administration of resveratrol (10 ppm) had no effect on body weight gain and tumor volume but produced striking reductions in the incidence (45%; P P in situ (7 of 7), whereas treatment with resveratrol suppressed DMBA-induced ductal carcinoma. Immunohistochemistry and Western blot analysis revealed that resveratrol suppressed the DMBA-induced cyclooxygenase-2 and matrix metalloprotease-9 expression in the breast tumor. Gel shift analysis showed suppression of DMBA-induced NF-κB activation by resveratrol. Treatment of human breast cancer MCF-7 cells with resveratrol also suppressed the NF-κB activation and inhibited proliferation at S-G 2 -M phase. Overall, our results suggest that resveratrol suppresses DMBA-induced mammary carcinogenesis, which correlates with down-regulation of NF-κB, cyclooxygenase-2, and matrix metalloprotease-9 expression.
445 citations
TL;DR: It is suggested that green tea and curcumin had inhibitory effects against oral carcinogenesis at the post-initiation stage and such inhibition may be related to the suppression of cell proliferation, induction of apoptosis and inhibition of angiogenesis.
Abstract: Tea is one of the most popular beverages consumed in the world. Curcumin, the major yellow pigment in turmeric, is used widely as a spice and food-coloring agent. In this study, we studied the effects of tea and curcumin on 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters. DMBA solution (0.5% in mineral oil, 0.1 ml) was applied topically to the left cheek pouch of male Syrian golden hamsters 3 times/week for 6 weeks. Two days after the last treatment of DMBA, the animals received green tea (6 mg tea solids/ml) as drinking fluid, or 10 mmol curcumin applied topically 3 times/week, or the combination of green tea and curcumin treatment, or no treatment for 18 weeks. The combination of tea and curcumin significantly decreased the oral visible tumor incidence from 92.3% (24/26) to 69.2% (18/26) and the squamous cell carcinoma (SCC) incidence from 76.9% (20/26) to 42.3% (11/26). The combination of tea and curcumin also decreased the number of visible tumors and the tumor volume by 52.4 and 69.8%, as well as the numbers of SCC, dysplasic lesions and papillomas by 62.0, 37.5 and 48.7%, respectively. Green tea or curcumin treatment decreased the number of visible tumors by 35.1 or 39.6%, the tumor volume by 41.6 or 61.3% and the number of SCC by 53.3 or 51.3%, respectively. Green tea also decreased the number of dysplasic lesions. Curcumin also significantly decreased the SCC incidence. Tea and curcumin, singly or in combination, decreased the proliferation index in hyperplasia, dysplasia and papillomas. Only the combination treatment decreased the proliferation index in SCC. Tea alone and in combination with curcumin significantly increased the apoptotic index in dysplasia and SCC. Curcumin, alone and in combination with tea, significantly inhibited the angiogenesis in papilloma and SCC. The results suggested that green tea and curcumin had inhibitory effects against oral carcinogenesis at the post-initiation stage and such inhibition may be related to the suppression of cell proliferation, induction of apoptosis and inhibition of angiogenesis.
211 citations
Journal Article•
TL;DR: ENL was demonstrated to act as a weak aromatase inhibitor in vitro and to reduce the relative uterine weight of the 7,12-dimethylbenz(a)anthracene-treated nonovariectomized rats, but in a short-term assay ENL had no effect on the uterine growth of the intact or androstenedione-treated immature rats.
Abstract: The inverse association between a high enterolactone (ENL) concentration in both urine and serum, and the risk of breast cancer found in epidemiological studies suggests a chemopreventive action for ENL. However, no causal relationship has been established in clinical studies or in experimental models for breast cancer. In the present study, the potential chemopreventive action of p.o. administered ENL (1 or 10 mg/kg of body weight) was tested in 7,12-dimethylbenz(a)anthracene-induced mammary cancers of the rat. Rats were maintained on a standard open-formula chow diet. Daily p.o. administration of ENL at a dose of 10 mg/kg of body weight for 7 weeks significantly inhibited tumor growth. The growth-inhibitory effect of ENL was more pronounced on the new tumors, which developed during the treatment period, but ENL also inhibited the growth of those tumors established before the start of the lignan administration. The rat serum concentration of ENL, which illustrated a permanent positive effect on breast cancer growth, was 0.4 microM, which is >10-fold as compared with the serum concentrations found in the general human population. The effect of ENL was not restricted to any specific histological tumor type. ENL was demonstrated to act as a weak aromatase inhibitor in vitro and to reduce the relative uterine weight of the 7,12-dimethylbenz(a)anthracene-treated nonovariectomized rats. However, in a short-term assay ENL had no effect on the uterine growth of the intact or androstenedione-treated immature rats. Thus, the mechanism of the ENL action and its minimum or optimal daily dose remains to be clarified.
98 citations
TL;DR: The role of P450 1a1 and 1b1 in the metabolic activation of DMBA in mouse epidermis is demonstrated and provides a mechanistic explanation for the differential effects of naturally occurring furanocoumarins (and 7,8-BF) on polycyclic aromatic hydrocarbon skin carcinogenesis.
Abstract: The current study was designed to determine the mechanistic basis for differences in the effects of naturally occurring furanocoumarins on skin tumor initiation by 7,12-dimethylbenz[a]anthracene (DMBA). Female SENCAR mice were pretreated topically with bergamottin, imperatorin, or isopimpinellin (100-3200 nmol), 7,8-benzoflavone (7,8-BF, 5-40 nmol, a known inhibitor of DMBA skin carcinogenesis in mice), or acetone (vehicle control) 5 min prior to topical treatment with DMBA (10 nmol). Imperatorin, isopimpinellin, and 7,8-BF, but not bergamottin, significantly blocked total DMBA-DNA adduct formation. HPLC analysis of DNA adducts revealed that bergamottin preferentially inhibited formation of anti-DMBA diol-epoxide (DMBADE) derived DNA adducts, imperatorin, and isopimpinellin inhibited both anti- and syn- derived adducts, whereas 7,8-BF showed some selectivity for reduction of syn-DMBADE-DNA adducts. Mouse embryo fibroblast C3H/10T1/2 (10T1/2) cells, and mouse hepatoma-derived 1c1c7 (Hepa-1) cells, which preferentially express P450 1b1 and P450 1a1, respectively, were co-incubated with 2 microM bergamottin, imperatorin, isopimpinellin, and 7,8-BF, and with DMBA (2 microM). Hepa-1 cells (P450 1a1) formed mainly anti-DMBADE-DNA adducts. In contrast, 10T1/2 cells (P450 1b1) formed mainly syn-DMBADE-DNA adducts. Bergamottin inhibited DMBA metabolism to DMBA-3,4-diol and blocked DNA adduct formation in Hepa-1 cells, but had little effect in 10T1/2 cells. In contrast, 7,8-BF completely blocked DMBA metabolism and DNA adduct formation in 10T1/2 cells, but had little effect in Hepa-1 cells. Imperatorin and isopimpinellin inhibited DMBA bioactivation in both cell lines. These results indicate that bergamottin is a more selective inhibitor of P450 1a1 and overall a less effective inhibitor of the metabolic activation of DMBA in mouse epidermis. In contrast, imperatorin, isopimpinellin, and especially 7,8-BF, which block metabolic activation of DMBA in mouse epidermis, appear more selective for P450 1b1. On the basis of our studies using 10T1/2 cells and Hepa-1 cells, it appears that P450 1a1 is primarily responsible for converting DMBA-3,4-diol to anti-DMBADE, whereas P450 1b1 is primarily responsible for converting DMBA-3,4-diol to syn-DMBADE. These data demonstrate the role of P450 1a1 and 1b1 in the metabolic activation of DMBA in mouse epidermis and provide a mechanistic explanation for the differential effects of naturally occurring furanocoumarins (and 7,8-BF) on polycyclic aromatic hydrocarbon skin carcinogenesis.
91 citations
TL;DR: The similarities in gene expression between PhIP- and DMBA-induced carcinomas raise the possibility that several molecular pathways for rat mammary gland transformation are maintained irrespective of the carcinogenic initiating agent.
Abstract: cDNA microarray analysis was used to examine gene expression profiles in normal female Sprague-Dawley rat mammary gland and in carcinomas induced by the cooked meat-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and the potent experimental carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Nine tubulopapillary carcinomas (five from PhIP-treated rats and four from DMBA-treated rats) and normal mammary gland from virgin, pregnant and lactating rats were examined on a rat 6.9k cDNA microarray. Although histologically identical, PhIP- and DMBA-induced carcinomas could be distinguished by hierarchical clustering and multi-dimensional scaling analyses of cDNA expression. In addition, the expression of 21 clones was statistically different between PhIP- and DMBA-induced carcinomas (F-test, P < 0.05). The data indicate that distinct chemical carcinogens induce unique gene expression patterns in mammary gland carcinomas. The specific chemical carcinogen-associated cDNA array profiles found in carcinomas may ultimately be applicable to better understanding cancer etiology. PhIP- and DMBA-induced carcinomas also shared similarities in cDNA expression profiles. By comparing the expression in carcinomas (PhIP plus DMBA induced) with normal rat mammary gland (at any stage of differentiation), 172 clones were found to be differentially expressed. Genes showing increased expression in carcinomas by cDNA microarray analysis (and further validated by immunohistochemistry and western blot analysis) include cyclin D1, PDGF-A chain, retinol binding protein 1, prohibitin and the transcription factor STAT5A. The similarities in gene expression between PhIP- and DMBA-induced carcinomas raise the possibility that several molecular pathways for rat mammary gland transformation are maintained irrespective of the carcinogenic initiating agent.
53 citations
TL;DR: Data indicate that isopimpinellin (and imperatorin) have chemopreventive effects when administered orally on skin tumor initiation by DMBA, and several parameters of systemic toxicity were evaluated following oral dosing.
Abstract: The current study was designed to evaluate the effects of oral administration of the citrus coumarin, isopimpinellin, on skin tumor initiation by topically applied benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA). To evaluate the effects of orally administered isopimpinellin on skin tumor initiation by B[a]P and DMBA, its effects on DNA adduct formation were first evaluated. Female SENCAR mice were pre-treated twice with corn oil, or isopimpinellin (70 mg/kg body wt per os) at 24 h and 2 h prior to topical treatment with B[a]P or DMBA. Another citrus coumarin, imperatorin, was also included in these experiments for comparison. Orally administered isopimpinellin and imperatorin significantly inhibited B[a]P-DNA adduct formation by 37 and 26%, respectively. Imperatorin also blocked DMBA-DNA adduct formation by 43%. In a second dose-response study, orally administered isopimpinellin (35, 70 and 150 mg/kg) blocked DMBA-DNA adduct formation by 23, 56 and 69%, respectively. For the tumor study, mice were pretreated orally with corn oil or isopimpinellin at 24 and 2 h prior to initiation with DMBA, and 2 weeks later promotion began with 12-O-tetradecanoylphorbol-13-acetate (TPA). Isopimpinellin significantly reduced the mean number of papillomas per mouse by 49, 73 and 78% compared to corn oil controls at 30, 70 and 150 mg/kg body wt, respectively. Orally administered isopimpinellin also significantly reduced the percentage of mice with papillomas at the highest dose tested (150 mg/kg). The effectiveness of isopimpinellin given topically over a broad dose range against DMBA tumor initiation was also evaluated for comparison. As part of this study, several parameters of systemic toxicity were evaluated following oral dosing with isopimpinellin and imperatorin. Mice were treated orally with corn oil, isopimpinellin or imperatorin (35, 70 and 150 mg/kg body wt per os) once daily for four consecutive days, killed at 24 h after the last dose, and livers, lungs, and kidneys evaluated histologically. In addition, urinary parameters of nephrotoxicity, blood parameters of liver and kidney function, and thrombin clotting time were assayed. No significant changes in blood clotting, or renal or hepatic function were observed. There was, however, a significant increase in liver wt accompanied by cytoplasmic vacuolation of hepatocytes. There were no histopathological changes in lungs or kidneys. Overall, these data indicate that isopimpinellin (and imperatorin) have chemopreventive effects when administered orally on skin tumor initiation by DMBA.
50 citations
TL;DR: This study investigated the molecular events that precede apoptosis in DMBA-treated 70Z/3 cells, a pre-B cell line, and proposed a novel PKR-dependent pathway for activation of apoptosis on the basis of caspase activity assays and immunoblotting techniques.
Abstract: Polycyclic aromatic hydrocarbons (PAHs) have been demonstrated to cause a variety of tumors and immunosuppressive effects. Our laboratory, and others, have demonstrated that coculture of progenitor B lymphocytes (pre-B cells) with bone marrow stromal cells and the model PAH 7,12-dimethylbenz[a]anthracene (DMBA) results in pre-B cell apoptosis. In this study we investigated the molecular events that precede apoptosis in DMBA-treated 70Z/3 cells, a pre-B cell line. Using caspase activity assays and immunoblotting techniques, we determined the temporal pattern of caspase expression in the pre-B cells. Using caspase inhibitors, we demonstrated that DMBA-mediated pre-B cell apoptosis is dependent on activation of caspase-8, whereas caspase-9 activation is essential for maximal apoptosis. We also demonstrated that DMBA activated PKR, an interferon-inducible protein kinase, in pre-B cells. PKR in turn can activate caspase-8 independently of death receptor ligation. As a result of these studies, we propose a novel PKR-dependent pathway for activation of apoptosis in DMBA-treated pre-B cells.
46 citations
Journal Article•
TL;DR: It is proved that IL-1alpha is induced by a carcinogenic DMBA dose and contributes to DMBA-induced inflammation and volume of CAs, hallmarks of tumor promotion and progression.
Abstract: Tumor-initiating properties of complete carcinogens such as 7,12-dimethylbenz( a )anthracene (DMBA) are well known but not the mechanism of DMBA-mediated tumor promotion. Our hypothesis is that interleukin (IL)-1α, an early proinflammatory cytokine that initiates a cascade of other cytokines and growth factors, is up-regulated by DMBA and contributes to inflammation and carcinogenesis. We found that topical exposure of SENCAR mice to a carcinogenic DMBA dose indeed triggers significant increases in mouse skin IL-1α and IL-1α mRNA. Five DMBA applications (200 nmol each) caused a statistically significant ( P = 0.02) increase in serum IL-1α, comparable with that induced by 12- O -tetradecanoylphorbol-13-acetate, a potent tumor promoter. IL-1α increase in serum was evident 24 h after the first DMBA application, whereas that in skin required five DMBA doses and became statistically significant ( P P = 0.0001) in skin and substantially decreased IL-1α in serum. Infiltration of polymorphonuclear leukocytes into skin was elevated 6-fold ( P = 0.002) and >10-fold ( P = 0.001) 24 h and 48 h after the fifth DMBA exposure, respectively. A pretreatment with anti-IL-1α Ab decreased polymorphonuclear leukocyte infiltration by >65% ( P P
42 citations
TL;DR: The results of the present study suggest that garlic may exert its chemopreventive effect by inducing apoptosis as revealed by the absence of neoplasms, induction of tTG and inhibition of Bcl-2 expression.
31 citations
TL;DR: A practical in vivo micronucleus test that used rat skin as the target organ and the effect of five skin carcinogens to determine the reproducibility and applicability of the method to mice was used.
Abstract: In a previous paper, we presented a practical in vivo micronucleus (MN) test that used rat skin as the target organ. To evaluate the test, as well as to determine the reproducibility and applicability of the method to mice, we used it to test the effect of five skin carcinogens (N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 4-nitroquinoline 1-oxide (4NQO), 7,12-dimethylbenz[a]anthracene (DMBA), and benzo[a]pyrene (B[a]P)) on rat and mouse skin. All five compounds significantly and dose-dependently increased the MN frequencies in the basal cells of the chemical-treated skin. These results indicated the reproducibility of the test results and also the applicability of the test to mice as well as rats.
30 citations
TL;DR: The finding that E2 and 4nOP at high doses caused reduction in mammary tumor development in female Tg and possibly non-Tg rats, may indicate that excess estrogen can exert a paradoxical inhibitory influence.
Abstract: Experiments were conducted to determine whether the natural estrogen and an environmental compound with estrogenic action, 4-n-octylphenol (4nOP), could modify tumor development in human c-Ha-ras proto-oncogene transgenic (Tg) rats which are highly susceptible to mammary and skin carcinogens. Female and male Tg and non-transgenic (non-Tg) rats were given a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) (25 mg/kg body weight) at 50 days of age and thereafter subcutaneously implanted with cholesterol pellets containing 0.01, 0.1 or 1.0 mg beta-estradiol 3-benzoate (E2) per rat or received diets containing 1000 or 100 p.p.m. 4nOP for 12 weeks in females or for 20 weeks in males. E2 reduced the mammary tumor incidence and multiplicity in a dose dependent manner, especially in female Tg rats. In contrast, E2 increased mammary tumor incidence and multiplicity at the lowest dose (0.01 mg), however it reduced skin tumor induction in male Tg rats. 4nOP at a dose of 100 p.p.m. decreased mammary tumor multiplicity in female Tg rats (P < 0.001). No effects were observed in males. In separate in vitro studies, E2 at low doses (10(-11)-10(-8) M) enhanced the growth of both MCF-7 and T47D cells and this was similarly the case for 4nOP at high doses (10(-7)-10(-5) M) in T47D cells. The finding that E2 and 4nOP at high doses caused reduction in mammary tumor development in female Tg and possibly non-Tg rats, may indicate that excess estrogen can exert a paradoxical inhibitory influence. E2 also appears to have bipotential effects in males, promoting mammary, but inhibiting skin carcinogenesis. These contrasting observations may be caused by differences in background physiological estrogen levels. In addition, the results suggest that Tg rats can be used in medium-term bioassay models to test for the modifying effects of estrogenic environmental compounds on mammary tumor development.
TL;DR: In the absence of PR, epithelial structures are resistant to the carcinogenic action of DMBA, and hyperplastic lesions were present only in glands of WT mice.
TL;DR: Results might suggest that dietary feeding of estrogenic compounds either synthetic (4-NP) or natural (GS) could act as an inhibitor of DMBA-induced rat ovarian carcinogenesis.
TL;DR: The results of the present study suggest that SAC may exert its chemopreventive effect by inducing apoptosis as revealed by the absence of neoplasms, induction of tTG and inhibition of Bcl‐2 expression.
Abstract: The apoptosis-inducing capacity of S-allylcysteine (SAC), a water-soluble garlic constituent, during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch (HBP) carcinogenesis was investigated in male Syrian hamsters using DNA fragmentation and the apoptosis-associated proteins, tissue transglutaminase (tTG) and Bcl-2. Hamsters were divided into four groups of six animals each. Animals in group 1 were painted with a 0.5% solution of DMBA in liquid paraffin on the right buccal pouches three times a week for 14 weeks. Group 2 animals painted with DMBA as in group 1, in addition received 200 mg kg−1 body weight SAC orally on days alternate to DMBA application. Group 3 animals received SAC as in group 2. Group 4 animals received neither DMBA nor SAC and served as the control. The experiment was terminated at the end of 14 weeks. Administration of SAC (200 mg kg−1 body weight) to animals painted with DMBA inhibited DMBA-induced HBP carcinogenesis as revealed by the absence of neoplasms, induction of tTG and inhibition of Bcl-2 expression. The results of the present study suggest that SAC may exert its chemopreventive effect by inducing apoptosis. Copyright © 2002 John Wiley & Sons, Ltd.
TL;DR: It is speculated that melatonin alone provides better chemoprevention against DMBA-induced oxidative stress than the vitamin E+selenium combination, and vitamin E plus selenium, and melatonin.
Abstract: Chemoprevention is a rapidly growing area of oncology that is identifying agents with a potentially preventive role in cancer. In this study, it was our goal to compare the chemopreventive effects of vitamin E plus selenium, and melatonin. Forty female mice were divided into four equal groups. The f
TL;DR: A statistical analysis revealed that differences exist among the various strains of mice in their response to CR, and confirmed that carcinogen-treated animals could be used to facilitate this aim by decreasing the time needed to observe differences in mortality kinetics.
Abstract: Calorie restriction (CR) has long been known to increase longevity and to delay the onset and to decrease the incidence of many age-related disease processes. The mechanism(s) by which these outcomes are attained is unidentified. This experiment was designed to examine whether differences existed in the extent to which various inbred strains of mice respond to CR. This work explored whether carcinogen-treated animals could be used to facilitate this aim by decreasing the time needed to observe differences in mortality kinetics between CR mice and ad libitum (AL) fed controls. Female mice from each of eight strains (A/J, BALB/c, C3H, C57BL/6, DBA/2J, FVB/J, NMRI, and 129/J) were given a single oral dose (65 mg/kg) of the carcinogen 7,12-dimethylbenz[a]anthracene and subsequently fed AL or calorically restricted. Following carcinogen treatment, the spectrum of lesions observed demonstrated genotypic variability, thereby complicating comparison among the inbred strains examined. However, in terms of the magnitude of alteration in mortality kinetics observed, a statistical analysis revealed that differences exist among the various strains of mice in their response.
TL;DR: It is suggested that the adrenocorticolytic effect of DMBA is the result of a dual mode of action, targeting both endothelial and parenchymal cells in the rat adrenal cortex and CYP1A1 presumably catalyses the activation in endothelial cells.
Abstract: 7,12-Dimethylbenz[a]anthracene (DMBA) is an adrenocorticolytic agent that causes apoplexy (haemorrhage) and massive necrosis in the adrenal cortex in rat. Several explanations regarding the origin of toxicity have been proposed. Huggins and Morii (J Exp Med 114:741–60, 1961) suggested that the cells of the inner adrenal cortex are the primary target, whereas Horvath and Kovacs (Pathol Eur 8:43–59, 1973) suggested the vascular endothelium as being the origin of toxicity. In the present study, cultured precision-cut tissue slices were used to localize target cells for irreversible [3H]DMBA binding in rat and mouse adrenal cortex. The sites of binding were confirmed by autoradiography in vivo. Irreversible [3H]DMBA binding was confined to zona fasciculata/reticularis cells in rat (but not in mouse) adrenal cortex. Pronounced binding was observed in clusters of cells (focal binding), localized predominantly in zona reticularis of rat. [3H]DMBA binding in zona fasciculata/reticularis cells was inhibited by the cytochrome P450 1A/B (CYP1A/B) inhibitors ellipticine, α-naphthoflavone, and 1-ethynylpyrene. The CYP11B1-inhibitor metyrapone did not reduce [3H]DMBA binding. In CYP1-induced (PCB 126-treated) rats and mice, intense irreversible [3H]DMBA binding was found also in endothelial cells of the adrenal cortex. The endothelial binding was abolished by the CYP1 inhibitors but remained unaffected by metyrapone. We conclude that the metabolic activation in adrenal parenchymal cells is presumably catalysed by CYP1B1, whereas CYP1A1 presumably catalyses the activation in endothelial cells. We suggest that the adrenocorticolytic effect of DMBA is the result of a dual mode of action, targeting both endothelial and parenchymal cells in the rat adrenal cortex.
TL;DR: Results suggest that iNOS expression of tumor and stromal cells is associated with the progression of DMBA-induced rat mammary tumors.
TL;DR: In a two-stage skin carcinogenesis model, mice initiated with 7,12-dimethylbenz[a]anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate for 12 weeks developed an average of 15.8 skin tumours per mouse with 100% tumour incidence.
Abstract: In a two-stage skin carcinogenesis model, mice initiated with 7,12-dimethylbenz[a]anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 12 weeks developed an average of 15.8 skin tumours per mouse with 100% tumour incidence. Topical application of polysaccharides from soybeans fermented with either Phellinus igniarius or Agrocybe cylindracea together with TPA twice weekly for 12 weeks inhibited the number of skin tumours per mouse by 70 or 88%, respectively, and the percentage of mice with tumours was lowered by 70 or 30%, respectively.
TL;DR: In this article, the Suzuki coupling reaction was used to synthesize important metabolites of 7,12-dimethylbenz[a ]anthracene (DMBA) and benzo[c ]chrysene (B[ c ]C).
TL;DR: It is suggested that maternal mEH plays a major role in DMBA-induced developmental toxicity, and embryonic mEH is less involved in the toxicity.
TL;DR: The hypothesis that DMBA administration decreases levels of GnRH mRNA in the preoptic area-anterior hypothalamus and GnRH receptor (GnRH Rc) mRNA and protein in the anterior pituitary gland is examined.
Abstract: A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of these tumors is preceded by a series of neuroendocrine disturbances, including attenuation of the preovulatory luteinizing hormone (LH) surge and amplification of the preovulatory 17β-estradiol surge, and gonadotropin-releasing hormone (GnRH) released in vitro. In this study, we examined the hypothesis that DMBA administration decreases levels of GnRH mRNA in the preoptic area-anterior hypothalamus (POA-AH) and GnRH receptor (GnRH Rc) mRNA and protein in the anterior pituitary gland. Sprague-Dawley rats, 55–60 days of age with regular estrous cycles, received a single dose of 15 mg DMBA in 1 ml sesame oil delivered by intragastric intubation. A first series of experiments was performed for the measurement of hypothalamic GnRH mRNA and pituitary GnRH Rc mRNA levels. A second series of experiments was performed for the measurement of pituitary GnRH receptor. In both experiments, animals were sacrificed by decapitation at 11.00, 16.00, 18.00 and 20.00 h on each day of the 7th or 8th estrous cycle (28–32 days) after treatment. GnRH and GnRH receptor mRNAs were quantified using solution hybridization-RNase protection assay. The GnRH Rc was quantified using the 125I-D-Ala6-N-Met-Leu6-des-Gly10-ethylamide GnRH. DMBA-treatment produced no significant effect on the overall mean values of GnRH mRNA. GnRH mRNA levels in control rats rose significantly between 16.00 and 20.00 h on proestrus and between 18.00 and 20.00 h on diestrus I. DMBA-treated rats had a surge in GnRH mRNA levels at 18.00 h on proestrus, and showed additional surges at 18.00 h on diestrus II and estrus. GnRH receptor mRNA content in the anterior pituitary gland surged at 16.00 h on certain days of the cycle in both groups of rats. In control rats, only the surge on diestrus II proved significant, whereas DMBA-treated rats exhibited significant surges on diestrus I, diestrus II and proestrus. GnRH receptor mRNA values were significantly lower on both days of diestrus in DMBA-treated rats compared with controls. GnRH Rc peptide content, like GnRH receptor in RNA surged at 16.00 h in both groups with the exception of a marked fall on proestrus day for DMBA treated rats. A reduction in the amplitude of the surge was also seen on the day of estrous and to a lesser extend on the day of diestrus DII in DMBA treated animal. Overall, there was a disruption of the GnRH Rc pattern which culminate on the day of proestrus in DMBA-treated animals. Interestingly, the daily rise between 11.00 and 16.00 h which is the more pronounced on the day of proestrus in control animals, was completely blunted in DMBA-treated rats. Overall, the results are consistent with the hypothesis that the carcinogen attenuates, directly or indirectly, preovulatory biosynthesis of the GnRH receptor and LH release.
TL;DR: A strong negative correlation between liver tumor incidence and persistence of [ 3 H]DMBA equivalents covalently bound to hepatic DNA suggested increased error-prone DNA repair at warmer temperature played an important role in increased tumor incidence.
Abstract: Temperature-modulated hepatic disposition, covalent binding of radiolabeled genotoxin to hepatic DNA, and cancer incidence in rainbow trout ( Oncorhyncus mykiss ) were assessed after a single exposure to 7,12-dimethylbenz[a]anthracene (DMBA). Fish (2 g) were acclimated at 10, 14, or 18°C for 1 mo and then exposed to 1 ppm DMBA in their water for 20 h. Exposures were at respective acclimation temperatures, or 10 and 18°C acclimated fish were shifted to 14°C for DMBA exposures. After 4 but not 20 h of exposure, hepatic [ 3 H]DMBA equivalents increased with temperature for fish exposed at their respective acclimation temperatures (10 or 18°C). Covalent binding of [ 3 H]DMBA to hepatic DNA was similar after 3 d in fish exposed at their respective acclimation temperatures. However, in fish exposed at 14°C, after 3 d the concentration of [ 3 H]DMBA covalently bound to hepatic DNA was higher in 10°C than 18°C acclimated fish. After 21 d, covalent binding of [ 3 H]DMBA to hepatic DNA was less persistent in 18°C t...
TL;DR: The effects of TAM pretreatment on mammary DNA adducts of the model carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), in the female rats suggest that TAM given to women prior to the development of breast cancer may modulate the impact of environmental exposures, for example, tobacco smoke.