Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis. (33/2118)

Prepubertal exposure to a pharmacological dose (500 mg kg(-1)) of the phyto-oestrogen genistein can reduce the incidence and multiplicity of carcinogen-induced mammary tumours in rats. However, such an exposure also disrupts the function of the hypothalamic-pituitary-gonadal axis, making it unsuitable for breast cancer prevention. We studied whether prepubertal exposure to genistein at a total body dose broadly comparable to the level typical of Oriental countries, approximately 1 mg kg(-1) body weight, affects mammary tumorigenesis. We also studied whether prepubertal exposure to zearalenone, a major source for phyto-oestrogens in the USA, influences breast cancer risk. Prepubertal rats were treated between postnatal days 7 and 20, with 20 microg (approximately 1 mg kg(-1) body weight) of either genistein or zearalenone. Zearalenone exposure significantly reduced both the incidence and multiplicity of mammary tumours induced by 7,12-dimethylbenz(a)anthracene (DMBA). Genistein exposure significantly reduced tumour multiplicity, but not tumour incidence, when compared with vehicle-treated animals. Furthermore, 60% of the tumours in the genistein group were not malignant, while all the tumours analysed for histopathology in the vehicle and zearalenone groups were adenocarcinomas. A higher number of differentiated alveolar buds, and lower number of terminal ducts, were present in the DMBA-treated mammary glands of the phyto-oestrogen exposed rats. The concentration of oestrogen receptor (ER) binding sites after the DMBA treatment was low in the mammary glands of all groups but a significantly higher proportion of the glands in the zearalenone exposed rats were ER-positive (i.e. ER levels > or = 5 fmol mg(-1) protein) than the glands of the vehicle controls. Our data suggest that a prepubertal exposure to a low dose of either zearalenone or genistein may protect the mammary gland from carcinogen-induced malignant transformation, possibly by increasing differentiation of the mammary epithelial tree.  (+info)

Exposure to flaxseed or its lignan component during different developmental stages influences rat mammary gland structures. (34/2118)

Reduction of the highly proliferative terminal end bud (TEB) structures in the developing mammary gland by differentiation to alveolar buds (ABs) and lobules has been suggested to be protective against mammary cancer. Flaxseed is high in alpha-linolenic acid (ALA) and secoisolariciresinol diglycoside (SDG). SDG is the precursor of mammalian lignans, which can affect mammary gland structures. Thus, the objective of this study was to determine the effect of lifetime, gestation and lactation or after-weaning exposure to 5 or 10% flaxseed or SDG and flaxseed oil components on the mammary gland structures of virgin female rat offspring at post-natal day 50. Lifetime or gestation and lactation exposure to flaxseed altered mammary gland structure development, whereas exposure to flaxseed after weaning had no effect. Lifetime or gestation and lactation exposure to 5% flaxseed caused endocrine changes, as suggested by delayed puberty onset and reduced number of estrous cycles. These changes reduced exposure to endogenous estrogens, leading to atrophy of mammary TEB structures. SDG, but not flaxseed oil, at the level found in 5% flaxseed produced similar effects as 5% flaxseed. This suggested that the lignans were the component in flaxseed responsible for the observed effects. Lifetime or gestation and lactation exposure to 10% flaxseed also caused endocrine changes, as suggested by early puberty onset and lengthened cycles due to prolonged estrus. This increased exposure to endogenous estrogens and stimulated mammary gland differentiation, as indicated by fewer TEBs and more ABs. Thus, lifetime or gestation and lactation exposure to 5 or 10% flaxseed induced structural changes in the mammary gland that may potentially reduce mammary cancer risk.  (+info)

Superovulation of immature hypothyroid rdw rats by thyroxine therapy and the development of eggs after in vitro fertilization. (35/2118)

The aim of this study was to examine the effect of thyroxine on ovulation in immature rdw rats and the fertilization and development of the eggs. Serum thyroxine concentrations at 30 days of age were significantly lower in rdw rats than in normal rats (P < 0.001), and greatly increased after thyroxine replacement therapy (P < 0.001). Although few eggs (1-5 +/- 1-2) were obtained from immature rdw rats treated with gonadotrophins alone, females treated with gonadotrophins and thyroxine ovulated significantly more eggs (85 +/- 5). As a control, normal littermates ovulated 21-45 eggs when treated with gonadotrophins alone, and 68 eggs when administered with gonadotrophins and thyroxine. Of the eggs collected from rdw rats treated with gonadotrophins and thyroxine, and inseminated with spermatozoa from mature F1 males, 98% were penetrated and in almost all (99%) of these eggs, male and female pronuclei formed. Forty-seven per cent of the pronuclear eggs developed to the blastocyst stage in vitro. After transfer to recipients, 21% (14/66) of one-cell and 22% (8/37) of two-cell embryos developed to offspring, and 62% (8/13) of pups were of rdw/rdw genotype. The average body weight (6.9 versus 7.8 g) of offspring derived from one-cell embryos was lower than that for two-cell embryos. The morulae and blastocysts did not develop to term, although 41% implanted in the uterine horns of recipients. In conclusion, in immature rdw rats, superovulation was induced by gonadotrophins combined with thyroxine therapy and the superovulated oocytes were fertilized and developed in vitro and developed to term after embryo transfer.  (+info)

Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice. (36/2118)

Ovariectomy in young, growing rodents results in decreased trabecular bone mineral density (BMD) and increased radial growth of the cortical bone. Both of these effects are reversed by treatment with estrogen. The aim of the present study was to determine the physiological role of estrogen receptor-beta (ERbeta) on bone structure and bone mineral content (BMC). The BMC was increased in adult (11 weeks old), but not prepubertal (4 weeks old), female ERbeta(-/-) mice compared with wild-type (WT) mice. This increase in BMC in females was not due to increased trabecular BMD, but to an increased cross-sectional cortical bone area associated with a radial bone growth. Male ERbeta(-/-) mice displayed no bone abnormalities compared with WT mice. Ovariectomy decreased the trabecular BMD to the same extent in adult female ERbeta(-/-) mice as in WT mice. The expression levels of osteoblast-associated genes - alpha1(I) collagen, alkaline phosphatase, and osteocalcin mRNAs - were elevated in bone from adult ERbeta(-/-) females compared with WT mice. These observations provide a possible explanation for the increased radial bone growth seen in female mutants, suggesting a repressive function for ERbeta in the regulation of bone growth during female adolescence. In summary, ERbeta is essential for the pubertal feminization of the cortical bone in female mice but is not required for the protective effect of estrogens on trabecular BMD.  (+info)

Pressure and volume overloads are associated with ventricular hypertrophy in male rainbow trout. (37/2118)

We investigated whether ventricular hypertrophy in reproductively mature male trout (Oncorhynchus mykiss) is associated with elevated hemodynamic loads. We measured ventral aortic blood pressure, pulse pressure dynamics, and blood volume in cannulated, unanesthetized trout with a wide range of relative ventricle masses (RVM, 0.076-0.199% of body wt). We also investigated in vitro pressure-volume dynamics in the bulbus arteriosus taken from trout with a wide range of RVMs. RVM was positively correlated with peak systolic pressure (SBP), mean blood pressure, and pulse pressure. Diastolic pressure and the absolute duration of arterial systole were similar among all animals, but a lower heart rate and a smaller relative duration of arterial systole were correlated with increasing RVM. Blood volume was expanded up to 34% as ventricles enlarged, and clearance of Evans blue dye was greater at higher SBP. Mass, maximal volume, and the pressure-volume dynamics of the bulbus were similar among all animals, suggesting that the bulbus did not compensate for ventricular enlargement. This conclusion was supported by the elevated maximal rates of arterial pressure development (+dP/dt) and decay (-dP/dt) observed as RVM increased. We conclude that 1) mature trout are hypertensive and hypervolemic, 2) the dynamics of the bulbus may contribute to increased afterload, and 3) these changes in hemodynamic load may promote ventricular hypertrophy.  (+info)

Germplasm evaluation in beef cattle--Cycle IV: postweaning growth and puberty of heifers. (38/2118)

Postweaning growth, puberty, and pregnancy traits were evaluated for 783 F1 heifers sired by Angus, Hereford, Charolais, Shorthorn, Galloway, Longhorn, Nellore, Piedmontese, and Salers bulls and out of Angus and Hereford dams in Cycle IV of the Germplasm Evaluation (GPE) Program at the U.S. Meat Animal Research Center. The Hereford and Angus sires included a sample of bulls born from 1982 to 1985 (1980s HA) as well as reference sires born from 1963 to 1970 (REF HA) used in previous cycles of the GPE program. Breed group of sire had a significant (P<.01) effect on age and weight at puberty, on 200-, 400-, and 550-d weights, on ADG from 200 to 400 and from 400 to 550 d, and 550-d hip height, but it did not influence (P<.05) pregnancy rate. Mean age and weight at puberty were predicted from the cumulative distribution because of censoring of data in each tail of the distribution. Sire breed group rankings (and predicted means in days) for age at puberty were as follows: Piedmontese (332), Shorthorn (338), Charolais (348), REF HA (348), Galloway (351), 1980s HA (352), Salers (355), Longhorn (357), and Nellore (405). Sire breed group rankings (and predicted means in kilograms) for weight at puberty were Longhorn (283), Piedmontese (298), Galloway (305), REF HA (309), Shorthorn (329), 1980s HA (330), Salers (338), Nellore (341), and Charolais (345). Sire breed group rankings (and least squares means in kilograms) for 200-d weight were Charolais (229), Salers (225), Nellore (221), Shorthorn (220), Piedmontese (215), 1980s HA (215), Galloway (209), REF HA (206), and Longhorn (197), with differences >8.3 kg significant. Rankings for 400-d weight (kilograms) were Charolais (390), Shorthorn (384), Salers (380), 1980s HA (374), Nellore (364), REF HA (356), Piedmontese (353), Galloway (348), and Longhorn (321), with differences >11.5 kg significant. Rankings for 550-d weight (kilograms) were Charolais (445), Salers (430), Shorthorn (429), 80's HA (422), Nellore (420), Piedmontese (401), REF HA (398), Galloway (389), and Longhorn (371), with differences >11.7 kg significant. Rankings for 550-d hip height (centimeters) were Nellore (132.2), Charolais (131.9), Salers (129.9), Shorthorn (129.5), Piedmontese (126.7), 1980s HA (126.1), Longhorn (125.3), Galloway (121.7), and REF HA (121.5), with differences >1.35 cm significant. Breed of sire had significant effects on growth and puberty traits of heifers.  (+info)

Laminin and beta1 integrins are crucial for normal mammary gland development in the mouse. (39/2118)

We have examined the role of integrin-extracellular matrix interactions in the morphogenesis of ductal structures in vivo using the developing mouse mammary gland as a model. At puberty, ductal growth from terminal end buds results in an arborescent network that eventually fills the gland, whereupon the buds shrink in size and become mitotically inactive. End buds are surrounded by a basement membrane, which we show contains laminin-1 and collagen IV. To address the role of cell-matrix interactions in gland development, pellets containing function-perturbing anti-beta1 integrin, anti-alpha6 integrin, and anti-laminin antibodies respectively were implanted into mammary glands at puberty. Blocking beta1 integrins dramatically reduced both the number of end buds per gland and the extent of the mammary ductal network, compared with controls. These effects were specific to the end buds since the rest of the gland architecture remained intact. Reduced development was still apparent after 6 days, but end buds subsequently reappeared, indicating that the inhibition of beta1 integrins was reversible. Similar results were obtained with anti-laminin antibodies. In contrast, no effect on morphogenesis in vivo was seen with anti-alpha6 integrin antibody, suggesting that alpha6 is not the important partner for beta1 in this system. The studies with beta1 integrin were confirmed in a culture model of ductal morphogenesis, where we show that hepatocyte growth factor (HGF)-induced tubulogenesis is dependent on functional beta1 integrins. Thus integrins and HGF cooperate to regulate ductal morphogenesis. We propose that both laminin and beta1 integrins are required to permit cellular traction through the stromal matrix and are therefore essential for maintaining end bud structure and function in normal pubertal mammary gland development.  (+info)

Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro. (40/2118)

Estrogenic isoflavones, such as genistein and daidzein, are present in virtually all natural-ingredient rodent diets that use soy as a source of protein. Since these compounds are endocrine-active, it is important to determine whether the amounts present in rodent diets are sufficient to affect sexual development. The present study consisted of in vitro and in vivo parts. In the in vitro portion, human hepatoma cells were transfected with either rat estrogen receptor (ER) alpha or beta plus an estrogen-responsive luciferase reporter gene. Genistein and daidzein were complete agonists at both ERs, genistein being more potent than daidzein, and both compounds were more potent at ER beta than ER alpha. In combined studies with estradiol, genistein exerted additive effects with estradiol in vitro. In the in vivo portion of the study, groups of six pregnant Sprague-Dawley females were fed one of the following four diets, and the pups were maintained on the same diets until puberty: (1) a natural-ingredient, open-formula rodent diet (NIH-07) containing 16 mg genistein and 14 mg daidzein per 100 g of feed; (2) a soy- and alfalfa-free diet (SAFD) in which casein and corn oil were substituted for soy and alfalfa meal and soy oil, respectively, that contained no detectable isoflavones; (3) SAFD containing 0.02% genistein (GE.02); or (4) SAFD containing 0.1% genistein (GE.1). In the GE.1 group, effects of dietary genistein included a decreased rate of body-weight gain, a markedly increased (2.3-fold) uterine/body weight (U/BW) ratio on postnatal day (pnd) 21, a significant acceleration of puberty among females, and a marginal decrease in the ventral prostate weight on postnatal day (pnd) 56. However, developmental differences among the groups fed SAFD, GE.02, or NIH-07 were small and suggested minimal effects of phytoestrogens at normal dietary levels. In particular, on pnd 21, the U/BW ratio of the GE.02 and NIH-07 groups did not differ significantly from that of the SAFD group. Only one statistically significant difference was detected between groups fed SAFD and NIH-07: the anogenital distance (AGD) of female neonates on pnd 1 whose dams were fed NIH-07 was 12% larger than that of neonates whose dams were fed SAFD. The results suggest that normal amounts of phytoestrogens in natural-ingredient rodent diets may affect one developmental parameter, the female AGD, and that higher doses can affect several other parameters in both males and females. Based on these findings, we do not suggest replacing soy- and alfalfa-based rodent diets with phytoestrogen-free diets in most developmental toxicology studies. However, phytoestrogen-free diets are recommended for endocrine toxicology studies at low doses, to determine whether interactive effects may occur between dietary phytoestrogens and man-made chemicals.  (+info)