“…The serum concentrations in animals fed the Purina 5008 diet was almost twice that of the other two diets. These values are at least 30,000-fold higher than the typical serum estrogen concentrations of adult mice, which are 15 to 30 pg/mL (Barkley et al, 1985;Butcher et al, 1974;Nequin et al, 1979).…”
Section: Serum and Urine Isoflavone Concentrations In Adult Mice Fed mentioning
SUMMARY:It is generally not known that most commercial rodent diets are formulated with soy protein and deliver large daily doses of isoflavones to animals throughout their lifespan, including the in utero period. Here, we demonstrate that isoflavones are bioavailable and show that commercial rodent diets universally used by animal facilities lead to very high steady-state serum isoflavone concentrations in adult rats (2613 Ϯ 873 ng/mL) and mice (2338 Ϯ 531 ng/mL), exceeding the animal's endogenous estrogen level by 30,000-to 60,000-fold. We demonstrate the maternal-fetal intrauterine transfer of isoflavones in animals fed a standard Purina 5001 soy-containing diet and show that newborn rat pups have high serum isoflavones levels (540 Ϯ 174 ng/mL) that are maintained throughout the suckling period by passage of isoflavones into maternal milk. These findings have profound implications for all animal experiments, including multigenerational studies and studies of transgenic animals, especially if biochemical or morphological end-points are influenced by the hormonal or nonhormonal properties of phytoestrogens. These compounds have the potential to modulate genotypic and phenotypic expression in general, and therefore, all investigators should be vigilant to the phytoestrogen composition of commercial rodent diets because there is a history of potent biological effects in larger animals and in humans from high circulating isoflavone concentrations. (Lab Invest 2001, 81:735-747).A lthough phytoestrogens are ubiquitous in the plant kingdom, it is soybeans and foods made with purified soy proteins that are by far the greatest contributors of isoflavones to animal and human diets (Coward et
“…The serum concentrations in animals fed the Purina 5008 diet was almost twice that of the other two diets. These values are at least 30,000-fold higher than the typical serum estrogen concentrations of adult mice, which are 15 to 30 pg/mL (Barkley et al, 1985;Butcher et al, 1974;Nequin et al, 1979).…”
Section: Serum and Urine Isoflavone Concentrations In Adult Mice Fed mentioning
SUMMARY:It is generally not known that most commercial rodent diets are formulated with soy protein and deliver large daily doses of isoflavones to animals throughout their lifespan, including the in utero period. Here, we demonstrate that isoflavones are bioavailable and show that commercial rodent diets universally used by animal facilities lead to very high steady-state serum isoflavone concentrations in adult rats (2613 Ϯ 873 ng/mL) and mice (2338 Ϯ 531 ng/mL), exceeding the animal's endogenous estrogen level by 30,000-to 60,000-fold. We demonstrate the maternal-fetal intrauterine transfer of isoflavones in animals fed a standard Purina 5001 soy-containing diet and show that newborn rat pups have high serum isoflavones levels (540 Ϯ 174 ng/mL) that are maintained throughout the suckling period by passage of isoflavones into maternal milk. These findings have profound implications for all animal experiments, including multigenerational studies and studies of transgenic animals, especially if biochemical or morphological end-points are influenced by the hormonal or nonhormonal properties of phytoestrogens. These compounds have the potential to modulate genotypic and phenotypic expression in general, and therefore, all investigators should be vigilant to the phytoestrogen composition of commercial rodent diets because there is a history of potent biological effects in larger animals and in humans from high circulating isoflavone concentrations. (Lab Invest 2001, 81:735-747).A lthough phytoestrogens are ubiquitous in the plant kingdom, it is soybeans and foods made with purified soy proteins that are by far the greatest contributors of isoflavones to animal and human diets (Coward et
“…Neither E 2 nor P plasma levels were affected by stress (F 1,37 ϭ 3.1, P Ͼ 0.5; and F 1,32 ϭ 1.1, P Ͼ 0.5, respectively). The steroid doses used in this study produced approximate E 2 and P blood levels observed during proestrus in regularly cycling female rats (40).…”
Section: Ovarian Steroid Concentrations In Experimental Ratsmentioning
It is well established that estrogens markedly enhance the glucocorticoid response to acute stress in females. However, the precise mechanism responsible for this regulation is poorly understood. Here, we tested whether estrogens enhance the activation of the paraventricular nucleus (PVN) of the hypothalamus by measuring stress-induced c-fos mRNA expression in the PVN of restraint-stressed ovariectomized (OVX) rats treated with physiologically relevant doses of estradiol (E 2), the major female estrogen. As expected, E2 enhanced plasma corticosterone responses to restraint in OVX females. However, E 2 markedly attenuated the stress-induced c-fos gene expression in the PVN and inhibited plasma ACTH responses in these animals. Furthermore, E 2-inhibitory effects were mimicked by progesterone (P) alone or in combination with E 2. Interestingly, the suppressive central effects of both E 2 and P were apparently independent of basal paraventricular corticotropin-releasing hormone (CRH) transcription, since these ovarian steroids did not significantly affect PVN CRH mRNA expression in unstressed rats. These unexpected findings suggested that E 2 promotes glucocorticoid hypersecretion in females by additional peripheral (i.e., adrenal) mechanisms. Indeed, E 2 markedly enhanced plasma corticosterone responses and adrenal corticosterone content in dexamethasone-blocked OVX rats challenged with varying doses of exogenous ACTH. These results suggest that enhanced adrenal sensitive to ACTH is an important physiological mechanism mediating E 2-related glucocorticoid hypersecretion in stressed females.corticosterone; progesterone; c-fos; adrenal; paraventricular nucleus THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS represents an important output in the neuroendocrine response to stress. This axis involves the coordinated activity of parvicellular neurons in the hypothalamic paraventricular nucleus (PVN), adrenocorticotropic hormone (ACTH)-secreting corticotropes in the anterior pituitary, and glucocorticoid-secreting cells in adrenal gland to bring together the neuroendocrine response to stress (1,48,55,56). Activity of the HPA axis is markedly influenced by sex steroids, as illustrated by the pronounced elevations in glucocorticoid levels exhibited in female rodents compared with male counterparts (7, 45). In ovariectomized (OVX) female rats, estradiol (E 2 ) potentiates the corticosterone response to numerous stressors, including restraint (60). Because E 2 -dependent glucocorticoid hypersecretion to a certain extent parallels elevations in ACTH, it is believed (3, 4) that estrogen acts centrally to modulate the neuroendocrine responses to stress.The central sites and mechanisms responsible for E 2 actions on the stress-induced glucocorticoid surge remain elusive. However, there is evidence that altered neuronal activity in the PVN might be involved in mediating E 2 effects on HPA axis responses to stress. In male rats, systemic injections of E 2 enhance the expression of the immediate early gene c-fos in response to novelty...
“…Table 1 presents mean serum levels of estradiol following our administration regime in comparison to levels reported for different stages of the estrous cycle and pregnancy (Nequin et al, 1979;Shaikh, 1971). …”
Section: Assessment Of Estradiol Serum Levelsmentioning
Women with schizophrenia have later onset and better response to antipsychotic drugs (APDs) than men during reproductive years, but the menopausal period is associated with increased symptom severity and reduced treatment response. Estrogen replacement therapy has been suggested as beneficial but clinical data are inconsistent. Latent inhibition (LI), the capacity to ignore irrelevant stimuli, is a measure of selective attention that is disrupted in acute schizophrenia patients and in rats and humans treated with the psychosisinducing drug amphetamine and can be reversed by typical and atypical APDs. Here we used amphetamine (1 mg/kg)-induced disrupted LI in ovariectomized rats to model low levels of estrogen along with hyperfunction of the dopaminergic system that may be occurring in menopausal psychosis, and tested the efficacy of APDs and estrogen in reversing disrupted LI. 17b-Estradiol (50, 150 mg/kg), clozapine (atypical APD; 5, 10 mg/kg), and haloperidol (typical APD; 0.1, 0.3 mg/kg) effectively reversed amphetamine-induced LI disruption in sham rats, but were much less effective in ovariectomized rats; 17b-estradiol and clozapine were effective only at high doses (150 mg/kg and 10 mg/kg, respectively), whereas haloperidol failed at both doses. Haloperidol and clozapine regained efficacy if coadministered with 17b-estradiol (50 mg/kg, an ineffective dose). Reduced sensitivity to dopamine (DA) blockade coupled with spared/potentiated sensitivity to DA stimulation after ovariectomy may provide a novel model recapitulating the combination of increased vulnerability to psychosis with reduced response to APD treatment in female patients during menopause. In addition, our data show that 17b-estradiol exerts antipsychotic activity.
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