Enhancement of mammary carcinogenesis by high levels of dietary fat: a phenomenon dependent on ad libitum feeding

Female 55-day-old Sprague-Dawley rats were treated with a single intravenous dose of 7,12-dimethylbenzanthracene (DMBA), 2 mg/100 g of body weight each. At 60 days of age, the rats were divided into four dietary groups (41-42 rats/group):I, 5% corn oil diet fed ad libitum; II, 20% corn oil diet fed ad libitum; III, 5% corn oil diet fed 12% less than group I; and IV, 20% corn oil diet fed 12% less than group II. The 5% and 20% corn oil diets were purified semisynthetic diets that were isonutrient on a caloric basis. All animals were housed individually in single cages; food consumption of each animal was computed daily throughout the study. Sixteen weeks after carcinogen treatment, mean numbers of mammary carcinomas per rat (+/- SE) in groups I, II, III, and IV were 4.1 +/- 0.6, 6.8 +/- 0.7, 3.0 +/- 0.3, and 4.1 +/- 0.5, respectively. Mean weight of mammary carcinomas per rat (g +/- SE) in groups I, II, III, and IV were 3.5 +/- 0.7, 8.0 +/- 1.3, 3.0 +/- 1.1, and 4.6 +/- 1.3, respectively. Mammary carcinoma number and weight were significantly (P less than .01) increased in the animals fed the 20% corn oil diet ad libitum when compared with those fed the 5% corn oil diet ad libitum; however, no significant differences in mammary tumor number or weight were observed between the animals fed a restricted, 20% corn oil diet and those fed a restricted, 5% corn oil diet. The study involving the animals fed the 12%-restricted diets was repeated (38-42 rats/group), with virtually identical results, i.e., the mean number of mammary carcinomas per rat in the groups fed the restricted 5% fat and 20% fat diets at termination of the study was 3.1 +/- 0.4 and 3.7 +/- 0.3, respectively, and the mean weight (g) of mammary carcinomas per rat was 4.3 +/- 1.2 and 4.0 +/- 1.1, respectively (no significant differences). Thus, high levels of dietary fat can significantly enhance mammary carcinogenesis in female rats, but only in animals on an ad libitum feeding protocol. A slight restriction in amount consumed (12% less than ad libitum) abolished the mammary carcinogenic differential between a high-fat and a low-fat diet.     

Effect of different levels of dietary trans fat or corn oil on azoxymethane-induced colon carcinogenesis in F344 rats

The effect of various levels of dietary corn oil or trans fat on azoxymethane (AOM; CAS: 25843-45-2)-induced carcinogenesis was investigated in female F344 rats fed the AIN-76 semipurified diets. Starting at 5 weeks of age, groups of rats were fed the low-fat diet containing 5% corn oil (designated as low-fat control diet). At 7 weeks of age, all animals except the vehicle-treated controls, were given sc injections of AOM (15 mg/kg body wt, once weekly) for 3 weeks. After 1 week, groups of animals were transferred to semipurified diets containing 13.6% corn oil and 23.5% corn oil or high-fat diets containing 5.9% corn oil plus 5.9% trans fat plus 11.8% Oleinate (low trans fat), 5.9% corn oil plus 11.8% trans fat plus 5.9% Oleinate (intermediate trans fat), and 5.9% corn oil plus 17.6% trans fat (high trans fat). Fecal bile acids were measured in vehicle-treated rats. All animals were necropsied 34 weeks after the last AOM injection. The animals fed the 23.5% corn oil diet had a higher incidence of colon tumors than did those in the groups fed the 5 and 13.6% corn oil diets. There was no difference in colon tumor incidence between the 5 and 13.6% corn oil diet groups. The animals fed the high-fat diets containing low trans fat, intermediate trans fat, and high trans fat developed significantly fewer liver and colon tumors and more small intestinal tumors than did the rats fed 23.5% corn oil diet. The excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid was higher in animals fed the 23.5% corn oil diet compared to the excretion in animals fed the other diets.     

Differential effects of tranylcypromine and imidazole on mammary carcinogenesis in rats fed low and high fat diets

Neoplastic development in the rat mammary gland can be suppressed by inhibition of the activity of several enzymes involved in eicosanoid biosynthesis. In order to investigate the potential utility of prostacyclin and thromboxane synthetases as targets for mammary cancer chemoprevention, experiments were conducted to determine the influence of tranylcypromine (TCP), an inhibitor of prostacyclin synthetase, and imidazole (IMI), an inhibitor of thromboxane synthetase, on mammary carcinogenesis induced in rats by N-methyl-N-nitrosourea. Fifty-day-old female Sprague-Dawley [Hsd:SD(BR)] rats received a single s.c. dose of 0 or 40 mg of N-methyl-N-nitrosourea per kg of body weight. Beginning 7 days after carcinogen administration, groups of rats were fed isoenergetic, casein-based diets containing 3 or 20% corn oil (w/w), supplemented with (per kg of diet) 10 mg of TCP, 1000 mg of IMI, or sucrose carrier only. TCP reduced mammary carcinoma multiplicity in rats fed the 20% corn oil diet, but had no effect in rats fed the diet containing 3% fat. By contrast, supplementation with IMI increased mammary cancer incidence in the group fed the 20% fat diet and increased carcinoma multiplicity in the 3% fat group to the levels seen in rats fed the 20% fat diet. These data suggest that inhibition of prostacyclin synthetase, but not thromboxane synthetase, may present a useful mechanism for mammary cancer chemoprevention in animals consuming a diet high in fat. Furthermore, the differential effects of TCP and IMI in rats fed low and high fat diets suggest that the action of dietary fat in mammary cancer induction may involve influences on the arachidonic acid cascade.     

Effects of dietary fat, calcium, and vitamin D on growth and mammary tumorigenesis induced by 7,12-dimethylbenz(a)anthracene in female Sprague-Dawley rats

This study was designed to test the influence of dietary calcium and vitamin D levels on the promotional effect of high-fat diets on chemically induced mammary carcinogenesis. In a small preliminary experiment (Experiment A), 40 female Sprague-Dawley rats, 43 days old, were randomly divided into 5 groups (8 rats/group) and fed a semipurified diet containing 3% sunflower seed oil (SF) by weight, 1.5 mg of calcium/kcal and 0.5 IU vitamin D/kcal of diet. After 1 week, each rat was given 2.5 mg of dimethylbenz(a)anthracene by gastric gavage. One week later, the animals were switched to 1 of 4 diets varying in fat (3 or 20% SF by weight), calcium (1.5 or 0.25 mg/kcal), vitamin D (0.5 or 0.05 IU/kcal), and phosphate or to a fifth diet containing 3% SF by weight, 0.1 mg of calcium/kcal and 0.05 IU of vitamin D/kcal. In all 5 diets, calcium:phosphate weight ratios were maintained at 1.2:1. In animals fed the high-fat diet, reduction of dietary calcium (1.5 to 0.25 mg/kcal) and vitamin D (0.5 to 0.05 IU/kcal) increased the incidence of mammary lesions from 37 to 75% and the total number of lesions from 4 to 16. A trend toward an increase in lesion weight and total lesion burden was also seen. To confirm these results, the experiment was repeated using the same protocol; 126 rats were divided into 6 groups, treated with dimethylbenz(a)anthracene, and fed the diets as described. A sixth diet was included that contained 20% SF by weight, 0.01 mg of calcium/kcal, and 0.05 IU of vitamin D/kcal. As for Experiment A, in animals fed the high-fat diet, reduction of dietary calcium (1.5 to 0.25 mg/kcal) and vitamin D (0.5 to 0.05 IU/kcal) resulted in an increase in total mammary lesions from 31 to 55, a significant increase in average lesion burden/rat with lesions (1.6 +/- 0.6 to 12 +/- 3 g), and a trend toward increasing weight of lesions. The effect was less obvious in animals fed the low-fat diet where, in both experiments, an increase in the incidence of mammary lesions was observed only when the dietary calcium was reduced from 1.5 to 0.1 mg/kcal. These data suggest that decreasing calcium and vitamin D increase the promoting effects of a high-fat diet on mammary tumorigenesis in the rat.     

Comparative effects of different animal and vegetable fats fed before and during carcinogen administration on mammary tumorigenesis, sexual maturation, and endocrine function in rats

The purpose of this investigation was to determine whether diets high in animal or vegetable fat affected mammary tumorigenesis when fed to rats only prior to and during the initiation phase of carcinogenesis. Weanling 21-day-old female Sprague-Dawley rats were divided into different dietary treatment groups and were allowed to feed and libitum on one of the following diets: 5% (normal fat) corn oil; 20% (high fat) corn oil; 20% palm oil; 20% beef tallow; or 20% lard. At 52 days of age, all rats were given p.o. 7.5 mg 7,12-dimethylbenz(a)anthracene (DMBA). One week following DMBA administration, all rats were switched to the 5% corn oil control diet and were maintained on this diet for the duration of the experiment. Rats fed a 20% lard diet during the treatment period showed a significant increase in mammary tumor incidence and number 19 weeks after DMBA administration, when compared to all other dietary treatment groups. Rats fed a 20% beef tallow diet during this same time period also demonstrated enhanced mammary tumor development, during the 10- to 19-week time period after DMBA. Mammary tumor development in rats fed 20% corn oil or palm oil diets during this treatment period was similar to that of normal fat controls. Estrogens are potent stimulators of mammary tumor growth and development in rats. Because mammary tumorigenesis was enhanced in rats fed high animal, but not vegetable fat diets, it was possible that estrogens present in animal fat might be responsible for this stimulation. Further studies demonstrated however, that increased mammary tumorigenesis in rats fed diets high in animal fat could not be explained on the basis of endocrine stimulation. Average day of vaginal opening for all groups fed 20% fat diets was similar and occurred earlier than in normal fat controls. In addition, 50- to 65-day-old rats in the different dietary treatment groups showed no differences in basal or surge levels of serum prolactin, luteinizing hormone, or estradiol. Rat diestrus uterine weight also showed no significant differences among dietary treatment groups. Thus diets containing high levels of animal fat caused little if any increased estrogenic activity in rats. In conclusion, high dietary intake of lard and beef tallow, but not vegetable fat, fed from weaning until only 1 week after DMBA administration, significantly enhances mammary tumorigenesis in rats. The mechanism(s) by which animal fat induces this stimulation is not clear, but it does not appear to result from endogenous or exogenous endocrine stimulation.     

Dietary fat versus caloric content in initiation and promotion of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats

Enhancement of mammary tumor formation by dietary fat may be mediated via increased caloric intake. Three experiments were performed to study this relationship in 7,12-dimethyl-benz(a)anthracene (DMBA)-treated female Sprague-Dawley rats: (a) high- or low-fat isocaloric diets were fed in a crossover design; (b) low-fat, high-calorie and high-fat, low-calorie diets were fed in a crossover design; (c) pair-fed rats were restricted to 60% of the calories of controls with ad libitum access to food beginning 10 days after DMBA administration. The pair-fed rats received daily 60% of calories, the same level of fiber, and 115% more fat than did rats fed ad libitum. Tumor yield but not tumor incidence was greater in rats fed high-fat rather than low-fat isocaloric diets prior to initiation of tumorigenesis. A low-fat, high-calorie diet led to more tumor incidence and yield than was associated with feeding of a high-fat, low-calorie diet. Caloric restriction (although with concomitant intake of more fat) led to complete inhibition of tumor formation. These results indicate that both high-fat and high-calorie diets exhibit cocarginogenic, not merely promotional, properties. Caloric intake may be a greater determinant than dietary fat of a tumor-enhancing regimen. Finally, restriction of caloric intake during promotion markedly suppresses tumor formation, despite the increased fat content of the restricted diet, suggesting a permissive role for calories in tumor formation. The possibility remains that alterations in levels of other dietary components could also have contributed to the observed effects.     

Influence of Esculetin on Incidence, Proliferation, and Cell Kinetics of Mammary Carcinomas Induced by 7,12-Dimethylbenz[α]anthracene in Rats on High- and Low-fat Diets

The effects of a high-fat diet and esculetin were investigated on 7,12-dimethylbenz[α]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats. Rats were given a 5-mg dose of DMBA. Seven days later, they were fed either a high-fat (20% soybean oil) or low-fat (0.5% soybean oil) diet. A half of the rats received diets containing 0.03% esculetin. Esculetin significantly inhibited tumor incidence, growth and cell kinetics of the tumor in the rats fed the high-fat and the low-fat diets. Our findings indicate that DMBA-induced mammary tumorigenesis is affected by lipoxygenase products.     

Promotion of azoxymethane-induced intestinal cancer by high-fat diet in rats.

Promotional properties of a high-fat diet in intestinal cancer were studied by feeding a 30% beef fat diet to 8 groups of rats (25 rats/group) for time periods varying from 1 to 21 weeks after 8 weekly s.c. injections of azoxymethane (AOM) (8 mg/ kg). Two other groups were fed the high-fat diet, one for 8 weeks prior to and the other during AOM injections. A 5% fat diet was fed to rats when not on the 30% fat diet and to a control group of 25 animals. High fat diet increased intestinal tumor frequency up to 2-fold when given for at least 4 weeks after but not during or prior to AOM injections; this increase occurred even after a prolonged interval (10 weeks) between the last AOM injection and the high-fat diet. In general, tumor frequency increased according to the length of time animals were fed the high-fat diet after AOM. Therefore, the high-fat diet in this model exhibited most of the properties of promoters developed from murine skin cancer, thus adding support to the concept that excess dietary fat acts at the promotional phase of carcinogenesis.     

Opposing effects of prepubertal low- and high-fat n-3 polyunsaturated fatty acid diets on rat mammary tumorigenesis

To determine whether dietary fat intake during childhood affects the later risk of developing breast cancer, we fed prepubertal rats between post-natal days 5 and 25 a low (16% energy) or high-fat (39% energy) diet composed mainly of n-6 or n-3 polyunsaturated fatty acids (PUFAs) originating either from corn oil or menhaden oil, respectively, in the ratios of 16-17:1 (n-6 PUFA diets) or 2-3:1 (n-3 PUFA diets). We also examined whether changes in risk are associated with perturbations in biological processes previously linked to fatty acid intake and breast cancer. Mammary tumorigenesis was induced by treating 50-day-old rats with the carcinogen 7,12-dimethylbenz[a]anthracene. When compared with the reference low-fat n-6 PUFA diet, prepubertal exposure to the low-fat n-3 PUFA diet decreased, whereas a high-fat n-3 PUFA diet increased mammary tumor incidence; the high-fat n-6 PUFA diet had no effect. Both the low and high-fat n-3 PUFA diets induced mammary epithelial differentiation by reducing the number of terminal end buds (TEBs) and increasing the presence of lobulo-alveolar structures. They also increased lipid peroxidation and reduced cyclooxygenase-2 activity. Prepubertal exposure to the low-fat n-3 PUFA diet increased apoptosis, determined using TUNEL assay, and reduced cell proliferation, determined using PCNA staining. In marked contrast, prepubertal exposure to the high-fat n-3 PUFA diet induced cell proliferation and inhibited apoptosis in the TEBs and lobular structures. The latter is consistent with the finding that pAkt, a survival factor that inhibits apoptosis, was elevated in their mammary glands. In summary, although prepubertal exposure to a low-fat n-3 PUFA diet reduced later mammary tumorigenesis in rats, high levels of this fatty acid can have adverse effects on the prepubertal mammary gland and increase subsequent breast cancer risk.     

Enhancement of pancreatic carcinogenesis by a dietary unsaturated fat in rats treated with saline or N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine

The effect of diets high in an unsaturated fat on the enhancement of pancreatic carcinogenesis in saline-treated rats and in rats treated with N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) was examined. Young male LEW rats were treated with a single dose of HPOP (160 mg/kg body wt) or saline, fed diets containing 5 or 20% corn oil, and then autopsied 12 months later. The pancreata of HPOP-treated rats fed the diet with 5% fat contained multiple foci and nodules of atypical acinar cells (AACN), acinar cell adenomas, and localized carcinomas. Rats fed the diet with 20% fat developed a similar spectrum of pancreatic lesions and also developed carcinomas that showed local invasion or metastasis to regional lymph nodes. The incidence and multiplicity of localized carcinomas was significantly higher in the group that was fed the high-fat diet. HPOP also induced neoplasms in the liver, lungs, and kidneys, but none of these had a higher incidence in the group fed the high-fat diet. Among rats that received no carcinogen, the incidence of AACN was high, but the multiplicity of these lesions was low, an average of three per pancreas in groups fed both levels of fat; however, the average area of AACN transections was larger in the high-fat diet group. One acinar cell adenoma and 1 carcinoma developed in the group of 11 rats fed the 20% corn oil diet, whereas no neoplasms developed in the group of 12 rats fed the 5% corn oil diet. Although the incidence of pancreatic neoplasms is not significantly different in these 2 groups, the data are consistent with the hypothesis that initiated foci are promoted to grow and become neoplasms in the pancreas of rats that are fed diets with a high content of unsaturated fat--as was demonstrated in the HPOP-treated rats.     

Similarity between trans fat and saturated fat in the modification of rat mammary carcinogenesis

Commercial hydrogenation of vegetable oils results in the introduction of trans fatty acids. In the present study, we have investigated the effect of feeding a fat which contained approximately 38% trans isomers (designated trans fat) on the induction of mammary tumors by dimethylbenz(a)anthracene in rats. The corresponding control fat (designated cis fat), which had a similar fatty acid composition, consisted of only cis isomers. Since both the trans and cis fats were rather saturated, a comparison was also made between these 2 types of fat and corn oil, which contains about 60% linoleic acid (C18:2). Each fat was present in the diet at 2 levels, 5 and 20% by weight. Although rats fed the 20% trans fat or cis fat diets had a slightly higher tumor incidence and yield than did those on the corresponding 5% fat control diets, the difference was not statistically significant. In contrast, rats fed the 20% corn oil diet developed a much greater number of tumors than did rats fed a diet containing only 5% corn oil. Further analysis of the data showed that diets containing either trans fat or cis fat were much less effective than were the corn oil diets in promoting the development of mammary neoplasia at either the 5 or 20% level. Our results thus suggest that trans fat behaves very much like a saturated fat in the modification of mammary tumorigenesis. A determination of the fatty acid content of the mammary fat pad indicated that its composition generally reflected the dietary fatty acid intake, with the incorporation of trans isomers into the mammary tissue found to be dependent on the quantity of trans fat in the diet.     

Effects of D,L-2-difluoromethylornithine and indomethacin on mammary tumor promotion in rats fed high n-3 and/or n-6 fat diets

Virgin female Sprague-Dawley rats (50 days of age) were administered a single intragastric 10-mg dose of 7,12-dimethylbenz(a)anthracene (DMBA). Twenty-one days later they were placed on diets containing either 20% corn oil (CO), 15% menhaden oil plus 5% corn oil (MO + CO), 20% CO plus 0.5% w/w of the irreversible ornithine decarboxylase inhibitor, D,L-2-difluoromethylornithine (CO + DFMO), 20% CO plus 0.004% w/w of the cyclooxygenase inhibitor indomethacin (CO + INDO), 20% CO + 0.004% INDO + 0.5% DFMO (CO + INDO + DFMO), or 15% MO + 5% CO + 0.5% DFMO (MO + CO + DFMO). The incidence of DMBA-induced mammary tumors was significantly reduced in rats fed diets containing DFMO but not in rats fed the diet containing indomethacin. Incidences of mammary tumors at 16 weeks post-DMBA were 86% in rats fed the CO diet, 83% in rats ingesting the diet containing CO + INDO, 28% in rats fed CO + DFMO, 32% in rats fed diet containing CO + INDO + DFMO, 59% in rats fed the MO + CO diet, and 24% in rats fed the MO + CO + DFMO diet. The average number of tumors and tumor burden per tumor-bearing rat were reduced and tumor latency was increased in all rats fed diets containing DFMO. Body weight gain, but not food intake, of rats fed the 20% fat + 0.5% DFMO diets was significantly less than in rats fed the 20% fat diets. Prostaglandin E and leukotriene (LTB4) syntheses, ODC activity and mammary tumorigenesis were significantly inhibited by feeding the diet containing menhaden oil or by adding 0.5% DFMO to any of the high fat diets. Feeding a 20% CO diet containing 0.004% INDO significantly reduced prostaglandin synthesis and ODC activity and increased LTB4 synthesis of mammary tumors but did not inhibit mammary tumorigenesis. This study suggests that the 5-lipoxygenase product LTB4 may be involved in mammary tumor production. Whereas a decrease in LTB4 appears to be associated with a decrease in tumorigenesis, an increase (as seen in the indomethacin group) was not associated with any change in the tumorigenic response.     

Dietary fat and mammary cancer. I. Promoting effects of different dietary fats on N-nitrosomethylurea-induced rat mammary tumorigenesis

The promoting effects of diets varying both in type and amount of fat on N-nitrosomethylurea [(NMU) CAS: 684-93-5]-induced mammary tumorigenesis were assessed in female inbred F344 rats. Two seed oils (safflower and corn) and two fruit oils (olive and coconut), varying widely in their diene, monoene, and saturated fatty acid ratios, were fed in the casein-based AIN-76A diets at 23% [high-fat (HF) diet] and 5% [low-fat (LF) diet] by weight, with the exception of coconut oil which was fed only at 23%. The predominant fatty acid in safflower and corn oils was linoleic acid (82 and 56%, respectively), while the predominant fatty acids in olive and coconut oils were oleic (79%) and myristic (54%), respectively. The test diets were fed beginning 2 days after administration of NMU and continued until termination of the experiment at 22 weeks post NMU administration. Analysis of tumor incidence, latency, and multiplicity data obtained from the 7 experimental groups indicated that animals fed the HF safflower and corn oil diets exhibited enhanced mammary tumor yields when compared to animals fed HF olive or coconut oil diets or their LF counterparts. Since weight gains and total caloric intake were similar in all 4 HF groups, the results of this study indicate that the tumor-promoting properties of HF diets are more of a function of differences in fatty acid composition than of fat content per se or of total caloric intake.     

Effects of high dietary fat on the growth and development of ovarian-independent carcinogen-induced mammary tumors in rats

This study examined the influence of high dietary fat intake on the development of ovarian-independent mammary tumors in both vehicle-treated controls and rats made deficient in estrogen and prolactin during tumor induction. The majority of 7,12-dimethylbenz(a) anthracene (DMBA)-induced mammary tumors in rats are dependent on estrogen and prolactin for growth, and suppression of prolactin and estrogen at the time of tumor initiation causes a reduction in tumor incidence and increase in tumor latency. However, the majority of mammary tumors which do develop in these animals exhibit ovarian-independent growth. Sprague-Dawley rats were given 7.5 mg DMBA p.o. at 57 days of age. Starting 1 day prior to and continuing for 7 days after DMBA administration, rats were given daily injection of vehicle or the combination of tamoxifen (20 micrograms/rat) plus bromocryptine (5 mg/kg). At the end of drug treatment, rats in each treatment group were equally divided and placed on normal fat (5% corn oil) or high fat (20% corn oil) diets for the duration of the experiment. Vehicle-treated rats were ovariectomized 27 wk and drug-treated rats 47 wk after DMBA administration to determine tumor ovarian dependency. Vehicle-treated rats fed high fat diets showed significant increases in mammary tumor incidence and number as compared to similarly treated rats fed a normal fat diet, with approximately 80% of the tumors in each group being ovarian dependent. Likewise, tamoxifen-bromocryptine-treated rats fed a high fat diet showed a significant enhancement in mammary tumor number, although not incidence, as compared to similarly treated rats fed a normal diet. Tumors in these drug-treated groups displayed essentially the same incidence of ovarian dependence (23%). Tamoxifen-bromocryptine-treated groups displayed a 2-fold increase in latency of tumor appearance as compared to vehicle-treated controls; however, this long latency was not reduced when these rats were fed a high fat diet. These results demonstrate that high dietary fat stimulates ovarian-dependent and -independent mammary tumorigenesis in rats but does not influence the hormonal responsiveness of these tumors.     

Effect of dietary fat on X-ray-induced mammary cancer in Sprague-Dawley rats

We studied the effect of dietary fat levels on the induction of mammary cancer by 350 rads total-body X-radiation given to noninbred albino Sprague-Dawley rats at 50 days of age. Compared to rats on a low-fat (LF) diet (5% lard), rats on a high-fat (HF) diet (20% lard) from 30 days of age had more tumors, with a higher multiplicity of carcinomas per rat. LF-fed groups exhibited a longer median tumor latency period thatn did HF-fed groups. A similar trend toward more tumors with an earlier time of death was seen in rats given single iv doses of 50 mg 1-methyl-1-nitrosourea/kg and fed an HF diet as compared to an LF diet.     

Large intestinal carcinogenesis. I. Promotional effect of dietary fatty acid isomers in the rat model

For evaluation of the promotional effects of dietary trans-fatty acids on large intestinal carcinogenesis, 120 inbred female F344 rats were divided into 6 groups and fed a 25% elaidic acid diet, a 25% oleic acid diet, or a regular (4.5% fat) chow diet. Ninety animals, 30 per dietary group, received weekly im injections of azoxymethane (2 mg/kg; CAS: 25843-45-2). None of the 30 saline-injected control animals, 10 per dietary group, fed any of the three diets developed tumors. There were twice as many animals with adenocarcinoma of the large intestine from the trans-fatty acid diet group as compared with either the cis-fatty acid diet group or regular diet groups. Chi-square analysis showed that the difference between the incidence of large intestinal carcinomas was not significant between the cis- and trans-fatty acid diets. The difference between the regular diet and trans-fatty acid diet groups was not significant at the 5% level (P = .08). A higher, but nonstatistically significant, incidence of nephroblastomas and squamous ear duct neoplasms was also observed in carcinogen-treated animals maintained on each of the high-fat diets as compared with the incidence of both in treated animals fed the regular chow diet.     

Net energy effects of dietary fat on chemically induced mammary carcinogenesis in F344 rats

The effect of net energy, as distinct from kilocalorie intake or the percent of fat in the diet, on 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6]-induced mammary tumorigenesis in female inbred F344 rats was investigated. Rats were fed a 5% corn oil diet from weaning until DMBA administration, when they were switched to one of three dietary regimens: 5% corn oil diet, low-fat diet fed ad libitum (LF); 30% corn oil diet, high-fat diet fed ad libitum (HF); or 30% corn oil diet fed at a level providing a calculated net energy equivalent to the group on LF [high-fat diet fed at a restricted level (HF-R)]. Calculated relative net energy values of the amounts of diet actually consumed by the groups on HF-R, LF, and HF were, respectively, 0.90, 1.00, and 1.07 (kcal equivalent to 34.1, 42.2, and 40.8, respectively). Weight gain for the groups on LF and HF-R was the same throughout the experiment (24 wk), while rats on HF weighed significantly more at 6 weeks and thereafter. Body composition analyses at 24 weeks established that the groups on HF and HF-R were equivalent in fat: protein ratio, whereas the group on LF had about 35% less body fat and 15% more body protein. Carcass energy was in the following order for rats in these diet groups: HF greater than HF-R greater than LF. At 24 weeks, tumor incidences for the groups on HF, LF, and HF-R were, respectively, 73, 43, and 7%. These data indicated that tumor appearance does not depend on the percent fat in the diet per se but rather on a complex interaction involving energy intake, energy retention, and body size.     

Effect of the prostaglandin synthetase inhibitor indomethacin on 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats fed different levels of fat

The effect of the prostaglandin synthetase inhibitor indomethacin on the dietary fat enhancement of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis has been examined in female Sprague-Dawley rats. Rats were fed either a normal-fat or high-fat diet (5 or 18% corn oil, respectively) with or without 0.004% indomethacin, starting 3 days after a single intragastric intubation of 5 mg 7,12-dimethylbenz(a)anthracene. Results of this experiment demonstrated that indomethacin completely blocked the stimulatory effect of fat on tumorigenesis, as measured by a decreased tumor incidence, a decreased number of tumors per group, a decreased tumor size, and an increased latency. No effect of indomethacin was observed in rats fed the normal-fat diet. These data suggest that at least part of the stimulatory effect of polyunsaturated fat on 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis may be mediated through an increased synthesis of prostaglandins.     

Influence of dietary retinyl acetate on normal rat mammary gland development and on the enhancement of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumorigenesis by high levels of dietary fat

The effect of high levels of dietary fat and retinyl acetate (ROA) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumor development and growth was examined. Female Sprague-Dawley rats, 51-53 days of age, were treated ig with 5 mg DMBA. At 55-57 days of age, the animals were divided into the following dietary treatment groups: A) 4.5% fat [control fat (CF)]; B) CF + 1.0 mmol ROA/kg diet (CF + ROA); C) 20.0% fat [high fat (HF)]; and D) HF + ROA. HF diets significantly increased mammary tumor multiplicity, with or without ROA, but did not significantly influence mammary tumor growth. ROA treatment reduced mammary tumor multiplicity regardless of the level of dietary fat and inhibited mammary tumor growth in the presence of normal levels of dietary fat. High levels of dietary fat did not significantly influence normal mammary gland growth and development. ROA significantly decreased normal mammary gland growth and development regardless of the level of dietary fat. Blood retinoids in rats fed ROA were primarily in the form of retinyl esters, i.e., retinyl linoleate, retinyl palmitate-oleate, and retinyl stearate. Free retinol levels in blood were not significantly influenced by ROA feeding. Blood retinyl ester levels were lower in rats fed the HF + ROA diet as compared to rats fed the CF + ROA diet.