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)

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.

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.

Genetic gains from reciprocal recurrent and within-line selection for egg production in the fowl.

Selection for survivors percent egg production from first egg to 40 weeks of age was conducted for six generations. Within-line selection (WLS) on the basis of an index of individual records plus sire family and dam family means was compared with reciprocal recurrent selection (RRS) based on sire family selection among cross progeny. Genetically heterogeneous synthetic populations, the Cornell Control and the Purdue Pool strains were used.The responses to WLS (3.84 °) and RRS (2.57 °) were both significantly greater than zero, but were not significantly different from each other. Nevertheless, the responses were proportional to their predicted values (.363 vs. 340). The advantage of WLS was due to the mechanics of selection resulting in slightly greater selection intensity and an increased correlation between the criterion of selection and the trait being improved. On the contrary, the RRS method had a slightly larger realized heritability as would be expected in the presence of non-additive genetic variance. Four of five pure-lines selected under both methods had statistically significant declines in performance due to inbreeding depression effects. All of the results observed are comparable with known genetic theory.Some problems in comparing genetic gains from different selection methods or selection criteria are discussed.