Dialectical behaviour therapy: effect of a coordinated implementation approach on programme sustainability.

Sustainability of DBT programmes and the factors which potentially influence this has received little attention from researchers. In this article, we review the literature reporting on sustainability of DBT programmes in outpatient settings. We also seek to advance the limited knowledge on this topic by reporting on the sustainability of DBT programmes delivered by teams that trained via a coordinated implementation approach in Ireland. As part of this perspective piece we conducted a systematic literature search which identified four studies reporting on DBT programme sustainability. All four reported on programmes delivered by teams that had received training as per the DBT Intensive Training Model. The findings of these studies are summarised and we consider the effect on DBT programme sustainability of introducing a coordinated implementation approach in Ireland.

Pattern of intake of food additives associated with hyperactivity in Irish children and teenagers.

A double-blind randomized intervention study has previously shown that a significant relationship exists between the consumption of various mixes of seven target additives by children and the onset of hyperactive behaviour. The present study set out to ascertain the pattern of intake of two mixes (A and B) of these seven target additives in Irish children and teenagers using the Irish national food consumption databases for children (n = 594) and teenagers (n = 441) and the National Food Ingredient Database. The majority of additive-containing foods consumed by both the children and teenagers contained one of the target additives. No food consumed by either the children or teenagers contained all seven of the target food additives. For each additive intake, estimates for every individual were made assuming that the additive was present at the maximum legal permitted level in those foods identified as containing it. For both groups, mean intakes of the food additives among consumers only were far below the doses used in the previous study on hyperactivity. Intakes at the 97.5th percentile of all food colours fell below the doses used in Mix B, while intakes for four of the six food colours were also below the doses used in Mix A. However, in the case of the preservative sodium benzoate, it exceeded the previously used dose in both children and teenagers. No child or teenager achieved the overall intakes used in the study linking food additives with hyperactivity.

Neutralizing antibodies to 500 microg interferon beta-1b: 28-month results of the IDEAS extension trial.

The Interferon Dose Escalation Assessment of Safety extension trial monitored neutralizing antibodies to interferon beta-1b in patients who currently or had previously received the double dose (500 microg) for up to 28 months. Fifteen patients entered the extension trial; five patients were neutralizing antibody-positive at the start of the trial. The present study demonstrates that when neutralizing antibodies develop in patients receiving higher doses of interferon beta-1b they tend to persist for a prolonged period, although neutralizing antibody titers tend to decrease over time and some patients may revert to neutralizing antibody-negative status.

Prevalence of hypertension in a hemodialysis population.

BACKGROUND: Accurate information on prevalence and status of blood pressure (BP) control in hemodialysis patients is lacking. Our Hemodialysis Quality Improvement Program, sought to determine: 1) The extent and control of hypertension (HTN), 2) whether Erythropoietin (EPO) dose or intradialytic fluid loss had any effect on BP and 3) a means to follow the severity of HTN. PATIENTS AND METHODS: The pre/post mid-week dialysis BP readings of 190 patients (64+/-14.1 years, 53% males, 77% whites) were evaluated over a 3 month period. HTN was defined as BP >150/90. Hypertension was further characterized according to whether the patients had normal or elevated pre-dialysis systolic, pre-dialysis diastolic, post-dialysis systolic or post-diastolic BP readings on more than 6 of the possible 13 recordings. The average EPO dose and weight loss during dialysis was correlated with BP. To better understand the extent of HTN, systolic and diastolic pressures were separately graded from 0 to 3 and a number designated as hypertension sensitivity index (HSI) was assigned to each patient. RESULTS: Of the 190 patients, 146 (76.8%) were hypertensive. 117 out of 146 hypertensive patients (80.1%) had persistent elevation of BP despite being on one or more antihypertensive medications. Most patients were on calcium channel blockers (39%) with 27% being on beta-blockers and 14% on Angiotensin converting enzyme inhibitors. There was no correlation between the number of medications used and the control of HTN. The dose of EPO also had no effect on the degree of HTN. 69.8% of all HTN was systolic. Of this, 64.7% was pre-dialysis and 35.3% post-dialysis. Multiple regression analysis demonstrated a significant correlation with loss of weight during dialysis and lowering of systolic BP (r = 0.33, p = 0.0001). The mean HSI for this population was 2.3+/-1.8. CONCLUSION: HTN was a frequent finding in our hemodialysis population and it was controlled in only 19.9% of hypertensive patients. Most of this HTN was pre-dialysis systolic. There was a significant correlation between fluid loss during dialysis and lowering of blood pressure. The use of the HSI has proven to be helpful in differentiating type and severity of HTN.

Mammary gland morphology and responsiveness to regulatory molecules following prenatal exposure to diethylstilbestrol.

Female ACI rats were exposed to diethylstilbestrol (DES) in utero to evaluate the effects on the peri-pubertal mammary gland with respect to 1) mammary gland morphology, 2) sensitivity to natural and synthetic estrogens, and 3) sensitivity to endogenous epidermal growth factor (EGF). Pregnant rats were injected with vehicle (sesame oil) or DES (total dose, 8.0 micrograms) on days 15 and 18 of gestation. DES-exposed and control offspring were ovariectomized at 34 days of age and sacrificed at day 53 to ascertain the morphology of the mammary glands in peri-pubertal rats. Elvax pellets containing 5 or 11 ng 17 beta-estradiol (E2) or DES were implanted subcutaneously adjacent to the third mammary gland pair. Furthermore, additional groups of rats were subjected to bilateral sialoadenectomy at the day of ovariectomy to remove the major source of endogenous EGF. A significant proportion of mammary glands of DES-exposed animals exhibited atypical mammary gland morphology, with approximately 25% displaying hypo-differentiation, and about 5% with aberrant hyper-proliferation. From the pellet implantation experiments, the DES-exposed glands were found to be refractory to stimulation by 5 and 11 ng DES; however, there was no significant difference in the degree of local stimulation elicited by either dose of E2. Sialoadenectomy at d34 had no apparent effect on mammary gland morphology in either the DES-exposed or vehicle-exposed groups. These data support the premise that the mammary gland of the peri-pubertal ACI rat is morphologically and physiologically aberrant as a function of transplacental exposure to DES, with a significant percentage hypo-differentiated and refractory to subsequent hormonal stimulation.

Morphological and physiological correlates of unilateral agenesis of the urogenital system in young ovariectomized ACI rats.

ACI rats are distinguished by a polygenic trait resulting in unilateral agenesis of the urogenital system in 20-30% of animals of both sexes. This report details additional features, both morphological and physiological, which distinguish ACI rats with unilateral agenesis of the reproductive and urinary tracts from the majority of ACI rats that have intact urogenital systems. Young female ACI rats were ovariectomized at 34 days of age and sacrificed 19 days later. A preliminary determination of the urogenital morphology was made at the time of ovariectomy and then confirmed by careful abdominal inspection at necropsy. Data on the time of vaginal opening were obtained at selected intervals prior to sacrifice. At necropsy, the mammary glands were removed and were prepared as stained whole mounts for morphological evaluation; the remaining portions of the reproductive tracts were excised, weighed, fixed, and sectioned for microscopic examination. A majority of animals with unilateral agenesis had mammary glands that had higher degrees of glandular proliferation than the mammary glands of intact rats. Unilateral agenesis animals also possessed significantly thicker and heavier uterine horns, despite having been ovariectomized. Furthermore, rats with unilateral agenesis were found to have an earlier time of vaginal opening than that of their intact counterparts. These features of ovariectomized ACI rats with unilateral agenesis are consistent with an active, extra-ovarian source of endogenous estrogen. Further investigation of the endocrinological state of animals with unilateral agenesis of the urogenital tract is warranted.(ABSTRACT TRUNCATED AT 250 WORDS)

Voluntary exercise and experimental mammary cancer.

The results of these studies indicate that voluntary activity suppresses the development of chemically and virally induced primary mammary tumors in rats and mice fed high-fat diets. These diets were chosen to mimic the current U.S. fat consumption of approximately 40% of calories as fat. It remains to be seen if activity exerts a similar suppressive effect on animals fed their customary low-fat diet (10% calories as fat). In general, the activity profiles of the female Fischer F-344 and Sprague-Dawley rat and the C3H/o mu j mouse exhibited a similar pattern with an early peak followed by a gradual plateau over time. The effects of activity on body fat composition showed a trend toward a decreased percent of body fat when compared to sedentary animals but a statistically significant decrease was found only in the F-344 female rat. In the DMBA model, carcinogen dose did alter outcome parameters. For example, time to first tumor was extended under low- but not high-DMBA conditions, and, conversely, tumor multiplicity was significantly decreased in the high- but not low-DMBA group. In the NMU model, an inverse association was found between the amount of activity and tumor incidence. A similar association was not found with the DMBA model. The reason for this is uncertain, but further analysis in terms of other parameters such as total tumor number may shed more light on this discrepancy. The suppressive effect of activity on the MMTV-induced mouse mammary tumor is of particular interest since it raises the possibility that activity may exert effects on the process of provirus insertion, and/or oncogene activation--an area of great potential promise in cancer prevention. Activity appeared to enhance the volume and to a lesser degree the number of metastatic foci in the lungs of F-344 retired breeders under high-fat but not medium-fat conditions. In addition, the most active animals in the high-fat group exhibited the greatest volume of metastases. These results, together with those in the NMU model, point to the critical importance of the quantity of voluntary activity an animal engages in and its relation to both primary and secondary cancer prevention. They imply that beyond a certain point of either frequency or intensity, the beneficial effect of exercise may be nullified by competing deleterious effects. The metastases study has also brought to light the importance of dietary fat as a potential intervening variable.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of reciprocal changes of diets differing in fat content on pulmonary metastasis from the 13762 rat mammary tumor.

The effect of changing the amount of polyunsaturated fat in the diet of aged female Fischer 344 rats at the time of tumor implant on metastasis from the 13762 transplantable mammary tumor was studied. Three experiments were performed. (a) Retired breeders, maintained on standard commercial chows until 10 to 12 mo of age, were transferred to high fat (HF, 23% corn oil) or low fat (LF, 5% corn oil) diets for 4 wk; at tumor implant, half of each group were kept on their original diets, while half were changed to the other diet (i.e., HF----HF, HF----LF, LF----LF, LF----HF). (b) Aged virgins, 14 to 16 mo old, were fed HF and LF diets from weaning; at tumor implant, the LF group stayed on the LF diet, while half the HF group remained on the HF diet and half were changed to LF. (c) Retired breeders were fed Purina rodent chow (5% mainly saturated fat) until tumor implant when they were placed on either the HF or LF diets. Six wk after tumor implant, all rats were necropsied, and the extent of pulmonary metastasis was determined. Data were expressed as volume of pulmonary metastases. In Experiment 1, animals maintained on a HF diet or changed to a HF diet at implant had significantly more pulmonary metastases than those animals kept on a LF or changed to a LF diet. Likewise in Experiment 2, pulmonary metastasis was less in rats which were fed a HF diet from weaning and then changed to LF at tumor implant than in the animals maintained on a HF diet both before and after tumor implant. Finally, in Experiment 3, when rats were changed from Purina rodent chow to either the HF or LF diet at tumor implant, there was no significant difference in the extent of pulmonary metastasis between the two groups; in both, the extent of metastasis was comparable to that seen in animals maintained on the LF corn oil diet. Data on metastasis were also examined in light of body weight, growth of the primary tumor, and food disappearance. These results suggest that the amount of fat consumed by aged rats after tumor implant is an important determinant of the extent of pulmonary metastasis from the 13762 mammary tumor. However, a period of prefeeding the semipurified diets appears to be required in order for the HF corn oil diet to stimulate metastasis in this system.

Effect of the quality of dietary fat on tumor growth and metastasis from a rat mammary adenocarcinoma.

Experiments were performed to investigate whether the type of dietary fat might affect metastasis from the 13,762 mammary tumor. Female Fischer 344 retired breeder rats were placed into one of five dietary groups: 23% (wt/wt) and 5% (wt/wt) corn oil (HFCO, LFCO), 20% (wt/wt) and 5% (wt/wt) olive oil (HFOO and LFOO), or 20% (wt/wt) beef tallow (HFBT). After four weeks on the diets, each rat had a 2-mm3 piece of the tumor subcutaneously implanted. Primary tumor growth and body weight were monitored weekly for 40 days. At necropsy, the average volume of pulmonary metastases in the HFCO animals (n = 30) was significantly greater than in the other four groups. Among the four groups that did not differ significantly from each other, the rank order in average volume of pulmonary metastasis was as follows: HFOO (n = 25), HFBT (n = 26), LFOO (n = 25), and LFCO (n = 18). Growth of the primary tumor did not vary appreciably among the five groups despite the significant difference in pulmonary metastasis volume. The diets varied considerably in fatty acid content; the most salient difference was that the HFCO diet, which stimulated metastasis significantly more than the other diets did, contained about four times more linoleic acid (18:2) than the other diets. The relevance of this difference and other fatty acid differences is discussed. These results suggest that the quality of dietary fat can be an important determinant of pulmonary metastasis from the 13,762 mammary tumor in retired breeder rats.

Effects of diethylstilbestrol exposure in utero on the genital tracts of female ACI rats.

Aspects of development and morphology were studied in the reproductive tract of female ACI rats exposed prenatally to diethylstilbestrol (DES) and followed to 10 months of age. Pregnant ACI rats were injected with vehicle or DES (0.8 microgram = low DES or 8.0 micrograms = high DES) on Days 15 and 18 of gestation. At 12 weeks of age, half of the female offspring in each prenatal exposure group received a subcutaneous implant of a pellet containing 2.5 mg DES and 17.5 mg cholesterol; the remaining offspring received a control cholesterol pellet. Maternal reproductive performance was significantly impaired in DES-treated dams compared to controls. In female offspring mean time of vaginal opening was accelerated from 50.3 +/- 2.7 days in the vehicle-exposed group to 46.2 +/- 2.6 and 47.1 +/- 2.3 days in the low and high DES groups, respectively. Prior to pellet implantation, none of the rats exposed to DES prenatally was in "persistent estrus." At necropsy, rats exposed to DES in utero and implanted with the cholesterol pellet showed an increased frequency of atypical uterine epithelia, cystically dilated uterine glands, and a thickened vaginal epithelium. Among groups implanted with the DES pellet, prenatal exposure to DES increased the incidence of squamous metaplasia of the luminal epithelium and of cystically dilated uterine glands. Collectively, groups implanted with the DES pellet had higher incidences of squamous metaplasia of the uterine lumen, cystically dilated uterine glands, and patches of multilayered uterine epithelium than groups bearing the cholesterol pellet. DES pellet-bearing rats were also found to display a pronounced thickening and vacuolation of the vaginal epithelium. Cervical tissue from 98% of the DES-treated litters was characterized by a markedly convoluted epithelium with numerous squamous cell nests. There were no apparent effects of prenatal DES exposure or postnatal DES treatment on ovarian or oviductal histology. However, ovarian wet weights were significantly reduced as a result of postnatal DES treatment. Thus, the epithelial tissues of the uterus, cervix, and vagina in the ACI rat show a sensitivity to DES whether administered prenatally, postnatally, or in combination.

Transplacental effects of diethylstilbestrol on mammary development and tumorigenesis in female ACI rats.

Female ACI rats were exposed to diethylstilbestrol (DES) transplacentally and followed to 10 months of age to assess the effect of the drug on mammary development and tumorigenesis. Pregnant rats were given injections of vehicle (sesame oil) or DES (total dose, 0.8 micrograms = low DES or 8.0 micrograms = high DES) on days 15 and 18 of gestation. Pellets containing 2.5 mg DES + 17.5 mg cholesterol (DES pellet) or 20 mg cholesterol (chol pellet) were implanted s.c. into 12-week-old female offspring, creating 6 experimental groups: vehicle exposure + chol pellet (1) or + DES pellet (2); low DES exposure + chol pellet (3) or + DES pellet (4); high DES exposure + chol pellet (5) or + DES pellet (6). At sacrifice, representative mammary tissue and all palpable mammary tumors were removed for histopathological analysis. Each of the 6 experimental groups contained a minimum of 32 rats from at least 14 litters. In computation of data, the unit of analysis was the litter. Groups which had received any DES (prenatally or postnatally) were found to have elongated nipples and enlarged pituitaries. The mammary gland whole mounts from all rats in groups 4 and 6 displayed extensive lobuloalveolar proliferation comparable to that seen in DES pellet controls (group 2). Mammary glands of approximately 75% of rats in groups 3 and 5 were categorized as showing the lowest grade of differentiation while this undifferentiated condition was seen in only 36% of group I controls. No palpable mammary tumors were found in rats exposed to vehicle in utero (group 1). But in group 5, a total of 6 tumors in 5 animals derived from 4 different litters were obtained, a difference shown to be statistically significant. Group 3 had 1 rat with 8 tumors. Among rats bearing the DES pellet, tumor latency was shortened significantly in both groups exposed to DES in utero. By 22 weeks after pellet implantation, 100% of the DES-exposed litters (groups 4 and 6) contained at least 1 tumor-bearing rat compared to about 50% of the tumor-bearing litters in group 2. Tumor multiplicity at sacrifice was increased significantly in the group exposed prenatally to the higher dose of DES. Histologically, the overwhelming majority of palpable mammary tumors from all tumor-bearing treatment groups were classified as adenocarcinomas. Prenatal exposure to DES did not alter the ratio of malignant to benign lesions observed, nor did it affect the degree of differentiation noted in the adenocarcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Stimulatory effect of high polyunsaturated fat diet on lung metastasis from the 13762 mammary adenocarcinoma in female retired breeder rats.

The effect of a high-fat (HF) diet (23% corn oil) on the growth and metastasis of the 13762 mammary tumor in Fischer 344 retired breeder (RB) and young virgin (YV) female rats was studied. The RB (10-12 mo old) and YV (8 wk old) rats were fed the HF or low-fat (LF) diet (5% corn oil) prior to and following tumor implantation for a total of at least 10 weeks. The growth rate of the primary tumor in the intact RB and YV was not affected by the HF diet. In RB rats ovariectomized 4 weeks prior to tumor implantation, the tumor grew significantly faster in the HF group as compared to the LF group. The total volume of metastatic tumor nodules in the lungs of the HF groups was significantly higher than that in the the lungs of the LF groups in both the intact and ovariectomized RB. In the YV, there was no difference in pulmonary metastatic burden between the HF and LF groups. The weights of the HF intact and ovariectomized RBs were higher than those of the LF animals. However, when pulmonary metastatic tumor burden was compared to body weight at implant or at sacrifice, there was no significant correlation in either the HF or LF groups. These results suggest that an HF diet enhanced the growth of pulmonary metastases in the intact and ovariectomized RB but not the YV rats and that the effect of the HF diet on pulmonary tumor burden cannot be attributed entirely to increased body weight.

Resistance to biological and chemical challenge in rodents treated with xerosin II, a natural product of Achromobacter xerosis.

The biological response-modifying activity of acid-precipitable material from Achromobacter xerosis was first described as suppression of viral pneumonia in mice. Later, this acid-precipitable material (xerosin) was found to have antiinflammatory activity and to induce tumor regression in chickens infected with Rous sarcoma virus. Here, we report further purification of xerosin resulting in a product (xerosin II) that retains high biological activity against viral and endotoxin-induced pneumonia in mice. In addition, we describe new activities of xerosin II in two rat tumor systems. Female CD rats received gastric intubations of 7,12-dimethylbenz(a)anthracene; 2 weeks later, half began 4 weeks of treatment with xerosin II, while others received saline only. Xerosin II treatment significantly delayed the appearance of the first palpable mammary tumors per rat. In female F344 rats implanted with the 13762 mammary tumor, 4 weeks of xerosin II treatment prolonged the survival of rats by an average of 5-11 days (12-24%) in two separate trials. Tumor growth and incidence of metastasis appeared unaffected by xerosin II treatment. Thus, this refined bacterial extract proved to be a potent biological response modifier in four different rodent systems.

Genital tract abnormalities in female rats exposed to diethylstilbestrol in utero.

Genital tract morphology in 14-month old female rats exposed prenatally to diethylstilbestrol (DES) was analyzed as part of an examination of the effects of transplacental exposure to DES on estrogen sensitive tissues. Pregnant Sprague-Dawley rats were injected with sesame oil alone or with DES in sesame oil on days 10 and 13 of gestation (total dose 1.2 micrograms DES) or on days 15 and 18 (total dose 1.2 micrograms or 120 micrograms DES). Female offspring (9-15 per group) were sacrificed at 14 months of age. Effects of DES exposure varied with the dose given and with the stage of differentiation of the fetal tissues. In the ovaries of rats exposed to 120 micrograms of DES on days 15 and 18 of gestation, follicular elements were reduced and replaced by dense sheets of stromal cells; oophoritis was noted in five of nine rats. Hypercellularity of oviductal stroma was another common feature, as was suppurative salpingitis. Ovaries of rats exposed to 1.2 micrograms DES on days 10 and 13 of gestation were more likely to contain numerous corpora lutea than the other DES-exposed groups of controls. An increased incidence of benign uterine abnormalities was observed in DES-exposed offspring, including squamous metaplasia and suppurative endometritis. In the cervices of all nine rats exposed to 120 micrograms DES on days 15 and 18 of gestation, the epithelial surface showed a convoluted pattern, lined by stratified squamous and stratified cuboidal cells. Thus, prenatal exposure to DES, especially at the higher dose used, has long-term consequences on reproductive tract morphology in Sprague-Dawley rats.

The influence of dietary fat on mammary tumor metastasis in the rat.

Young, virgin female Fischer 344 rats bearing the 13762 transplantable mammary tumor were fed diets containing either 5% (low-fat group) or 23% (high-fat group) corn oil for five weeks before and six weeks after tumor implantation. Animals in the two diet groups gained weight at comparable rates throughout the experiment. There was no significant difference between the low-fat and high-fat groups with respect to average tumor diameter measured twice per week for six weeks. At the time of death (6 weeks after tumor implantation), the lungs of all rats in both diet groups contained some metastatic tumor deposits; the volume of the metastases in the lungs varied widely in both groups. Numbers of metastases to regional lymph nodes and kidneys appeared unaffected by the fat content of the diet. Thus, both growth of the 13762 mammary tumor itself and metastatic spread from the tumor were comparable whether the young rats were fed a high-fat or a low-fat diet.

Transplacental action of diethylstilbestrol on mammary carcinogenesis in female rats given one or two doses of 7,12-dimethylbenz(a)anthracene.

Aspects of the development, morphology, and estrogen binding capacity of mammary tumors in rats exposed prenatally to the synthetic estrogen, diethylstilbestrol (DES), and treated postnatally with 7,12-dimethylbenz(a)anthracene (DMBA) were analyzed as part of a project aimed at understanding the effects of transplacental exposure to DES on estrogen-sensitive tissues. Pregnant Sprague-Dawley rats were given injections of DES (total dose, 1.2 micrograms) or vehicle alone on Days 15 and 18 of gestation. All female offspring were given gastric intubations of DMBA, either a single 10-mg dose on Day 50 or two doses (10 mg each) on Days 50 and 57. Among rats treated postnatally with 10 mg of DMBA, the DES-exposed group had a significantly greater incidence of palpable mammary tumors than did the vehicle-exposed controls. In addition, there was an earlier time of appearance of palpable tumors in the DES-exposed group. When the data from rats treated postnatally with two 10-mg doses of DMBA were analyzed, there were no significant differences in palpable mammary tumor incidence or tumor latency between the DES-exposed and vehicle-exposed groups. When the pathology of the mammary tumors produced in rats treated with 10 mg of DMBA was analyzed, the DES-exposed group had a significantly higher proportion of benign tumors (fibroadenoma, adenoma, lobular hyperplasia) than adenocarcinomata compared to vehicle-exposed controls. Both exposure groups had similar numbers of nonpalpable mammary lesions discovered at necropsy. Estrogen binding capacities of representative adenocarcinomata did not differ significantly between the two prenatal exposure groups treated postnatally with 10 mg of DMBA. These results demonstrate the importance of the dose of the challenge carcinogen in revealing the effects of transplacental drug exposure and may have special significance for women who were exposed to DES in utero.

Influence of prenatal exposure to diethylstilbestrol on estrogen and progestin binding proteins in uteri and dimethylbenzanthracene- induced mammary tumors of the rat.

Various characteristics of steroid binding proteins from mammary tumors and uteri of rats exposed prenatally to diethylstilbestrol (DES) were examined. Pregnant rats were treated with no hormone (group A) or with a total dose of 1.2 micrograms DES during the second (group B) or third (group C) trimester of gestation. Female offspring received 7,12-dimethylbenz[a]anthracene (DMBA) at d 50 +/- 1. Animals with large mammary tumors were subjected to bilateral ovariectomy. Seven months after carcinogen treatment, the experiment was terminated. High-affinity binding sites for [3H] estradiol-17 beta and [3H]R5020 were found in all mammary tumors assayed. On sucrose gradients of low ionic strength both 8S and 4S forms of the estrogen receptor were identified in mammary tumors, regardless of prenatal treatment. In addition, progestin receptors sedimenting at 4S were identified in these tumors. However, the 7-8S form of the progestin receptor was found only in tumors from intact animals. Levels of progestin receptors were diminished after ovariectomy, both in mammary tumors and in uteri; ovariectomy also resulted in a significant reduction in uterine wet weight in the hormone exposure groups, as expected. Unlike groups A and B, rats exposed to DES during the third trimester had uterine progestin binding capacities and uterine wet weights that did not decrease proportionally ater ovariectomy. Furthermore, progestin binding capacities in mammary tumors from group C ovariectomized rats were higher than those in the other two groups. In intact rats from group C, cytosol from mammary tumors also had elevated levels of progestin binding; however, no differences in progestin binding were observed in the uteri from these animals. Small differences in estrogen binding capacities in tumor tissues were observed among the three groups; uterine estrogen binding capacities did not vary significantly. Prenatal exposure to DES during the third trimester appeared related to persistent biochemical alterations in rat mammary tumors and uteri; earlier exposure did not have this effect.

Prenatal exposure to diethylstilbestrol: ovarian-independent growth of mammary tumors induced by 7,12-dimethylbenz[a]anthracene.

The effects of ovariectomy on the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were investigated after rats ahd been exposed prenatally to diethylstilbestrol (DES). Pregnant rats were inoculated with either DES (total dose: 1.2 micrograms) in sesame oil or with the vehicle alone on days 10 and 13 of gestation. Female offspring were given 2 gastric intubations of DMBA (10 mg each) 1 week apart beginning at 50 plus or minus 1 days of age. When the average diameter of a mammary tumor exceeded 2 cm, the animal was ovariectomized. The initial response of most tumors in both the DES-exposed and control groups to ovariectomy was size regression. The growth of 7 tumors that arose soon after DMBA treatment in each group was studied for 12-20 weeks after ovariectomy. Whereas only 1 tumor from the control group resumed active growth after the initial regression period, 6 tumors in the DES-exposed group overcame the initial effects of ovariectomy and began to grow again. Thus ovariectomy appeared to be less effective in producing sustained control growth in DMBA-induced mammary tumors in rats exposed prenatally to DES.

Mammary tumorigenesis in the rat following prenatal exposure to diethylstilbestrol and postnatal treatment with 7,12-dimethylbenz[a]anthracene.

Pregnant rats were injected with vehicle or 1,2 microgram diethylstilbestrol (DES) during wk 2 or 3 of gestation; their female offspring ( approximately 50 d old) were fed 7,12-dimethylbenz[a]anthrocene (DMBA). The survivors (27 per group) were sacrificed 30 wk later. The three groups did not differ in the number of tumor-bearing animals; however, significantly more palpable mammary tumors arose in both DES-exposed groups than in controls. When DES was given during the second trimester, palpable tumors appeared earlier than in the other two groups. Thus, transplancental exposure to DES potentiated the action of a known carcinogen (DMBA) on rat mammary tissue. These results raise the possibility that, for young women, DES exposure in utero may have affected tissues other than the vagina. Further investigation is warranted, with special emphasis on the effects of DES on mammary and other estrogen-sensitive tissues.