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Lack of evidence for endocrine disrupting effects in rats exposed to fenitrothion in utero and from weaning to maturation.

Fenitrothion is a broad-spectrum organophosphate insecticide. Recently, it has been reported to exert androgenic or anti-androgenic activity in in vitro and in vivo screening assays, although the effects appear equivocal in vivo. To provide a conclusive and comprehensive evaluation of fenitrothion, especially regarding its anti-androgenic activity in the reproductive and endocrine systems, we conducted a one-generation reproductive toxicity study at appropriately toxic dose levels with a number of sensitive endpoints for endocrine disruption. Fenitrothion was administered to Crj:CD(SD)IGS parental animals (P) at concentrations of 10, 20, and 60 ppm in the diet for 10 weeks prior to mating, and throughout mating, gestation and lactation. Their offspring (F1) were exposed from weaning until maturation at the age of 10 weeks. In the P generation, brain cholinesterase activity was remarkably reduced in the 60 ppm males and in the 20 and 60 ppm females. Reproductive performance, organ weights, histopathology, and sperm analytical parameters were not affected. In the F1 generation, no general toxicity or effects on anogenital distance, retention of areolae/nipples, onset of puberty, organ weights, histopathological findings, and sperm parameters were observed. In conclusion, fenitrothion had no effects on the reproductive or endocrine systems of the P and F1 generations, even at toxic doses that markedly suppressed brain cholinesterase activity in P animals. The results suggest that fenitrothion at in-use levels in the environment is unlikely to cause disruption of human endocrine systems.

Acetylcholinesterase↗

[Study of the effect of a dexamethasone-containing antirheumatic on the hypothalomus-adenohypophysis-adrenocortical system].

The aim of this study was to investigate the effect of an analgesic-antirheumatic fixed combination drug containing dexamethasone (Ambene) on this endocrine system. 10 healthy volunteers received an intramuscular injection of Ambene as either single dose once, single dose on three consecutive days or on three alternating days. Early morning ACTH plasma concentrations, endogenous cortisol profiles and dexamethasone kinetics were determined and insulin-hypoglycemia tests stimulated stress conditions before, during and after Ambene-application. In all cases treatment led to short-term suppression of the reactability of the Hypothalamus-Anteropituitary Corticoadrenal System. Three days after single dose or alternating day administration for three days reactions of this endocrine system were completely restored, while after administration on three consecutive days there still was a slight decrease in basal and insulin-stimulated cortisol values. The short half-life of water soluble dexamethasone in Ambene appears to be the reason for the rapid restitution of this endocrine system.

Adrenocorticotropic Hormone↗

Immunoregulatory role of endogenous catecholamines synthesized by immune cells.

It has been well known that catecholamines (CAs) in the body, including norepinephrine (NE), epinephrine (E) and dopamine (DA), are synthesized and secreted by neurons and endocrine cells and mainly modulate visceral activities such as cardiovascular, respiratory and digestive functions. The studies over the past nearly 30 years have shown that CAs can also regulate immune function. The immunomodulation of CAs is generally considered as a role mediating the regulation of nervous and endocrine systems. However, recent studies reveal that immune cells can also synthesize CAs, which is an update of traditional concept. A classical metabolic pathway of CAs shared by the nervous and endocrine systems is present in the immune cells, i.e., the immunocytes have the enzymes for synthesis of CAs [e.g. tyrosine hydroxylase (TH)] and the enzymes for degradation of CAs [e.g. monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)]. The endogenous CAs synthesized by immune cells can regulate many immune functions, including cellular proliferation, differentiation, apoptosis and cytokine production. These roles of the endogenous CAs may be mediated by an autocrine/paracrine pathway via relevant receptors on the immunocytes and intracellular cAMP. Intracellular oxidative mechanism may also be involved in immunoregulation of endogenous CAs in immune cells. In addition, some metabolic abnormalities of CAs in the immune cells probably induce some autoimmune diseases, such as multiple sclerosis (MS) and rheumatoid arthritis. These findings not only provide evidence for the new concept that the immune system is possible to become the third CA system other than the nervous and endocrine systems, but also extend our comprehension on functional significance of the endogenous CAs synthesized by immune cells.

Animals↗

Ethanol-fed Sprague-Dawley rats maintain normal levels of insulin-like growth factor I.

Ethanol-fed rats do not gain weight as fast as their isoenergetically pair-fed controls; the reasons for this slower rate of growth remain uncertain. Insulin-like growth factor I (IGF-I) is a major component of the growth-promoting endocrine system. To determine whether ethanol impairs growth by interfering with this component of the endocrine system, rats were pair-fed ethanol-containing and control liquid diets. When rats were meal-fed on the day before the experiment there were no differences in serum IGF-I concentrations or hepatic IGF-I mRNA levels between ethanol-fed and control animals after 2, 3 or 4 wk. These results indicate that ethanol consumption per se does not interfere with IGF-I production and that energy derived from ethanol sustains this component of the growth-promoting endocrine system as well as carbohydrate energy. The schedule used to administer the diets, however, did have a significant effect on hepatic IGF-I mRNA levels. When after 4 wk of dietary treatment rats were not meal-fed but received their entire dietary ration in a single morning feeding on the day before the experiment, the ethanol-fed animals had significantly higher hepatic IGF-I mRNA levels than their pair-fed controls. This finding indicates that these animals are nutritionally dissimilar despite isoenergetic pair-feeding.

Animals↗

Mysid crustaceans as potential test organisms for the evaluation of environmental endocrine disruption: a review.

Anthropogenic chemicals that disrupt the hormonal systems (endocrine disruptors) of wildlife species recently have become a widely investigated and politically charged issue. Invertebrates account for roughly 95% of all animals, yet surprisingly little effort has been made to understand their value in signaling potential environmental endocrine disruption. This omission largely can be attributed to the high diversity of invertebrates and the shortage of fundamental knowledge of their endocrine systems. Insects and crustaceans are exceptions and, as such, appear to be excellent candidates for evaluating the environmental consequences of chemically induced endocrine disruption. Mysid shrimp (Crustacea: Mysidacea) may serve as a viable surrogate for many crustaceans and have been put forward as suitable test organisms for the evaluation of endocrine disruption by several researchers and regulatory bodies (e.g., the U.S. Environmental Protection Agency). Despite the long-standing use of mysids in toxicity testing, little information exists on their endocrinology, and few studies have focused on the potential of these animals for evaluating the effects of hormone-disrupting compounds. Therefore, the question remains as to whether the current standardized mysid endpoints can be used or adapted to detect endocrine disruption, or if new procedures must be developed, specifically directed at evaluating hormone-regulated endpoints in these animals. This review summarizes the ecological importance of mysids in estuarine and marine ecosystems, their use in toxicity testing and environmental monitoring, and their endocrinology and important hormone-regulated processes to highlight their potential use in assessing environmental endocrine disruption.

Animals↗

Growth hormone administration to long-living dwarf mice alters multiple components of the antioxidative defense system.

Endocrine hormones are thought to be involved in processes that contribute to aging. Long-living dwarf mice are growth hormone (GH)-deficient and exhibit enhanced expression of antioxidative defense molecules when compared to normal, wild type littermates. In this study, 3- and 12-month-old Ames dwarf mice received with 50 microg GH or saline for 7 days. Tissues were collected and assayed for several antioxidant molecules. In addition to increased body and liver weights, GH treatment of dwarf mice decreased liver, kidney and heart catalase protein (P < 0.05). Catalase activity was significantly decreased in kidney and heart tissues of mice receiving GH compared to dwarf mice treated with saline. Glutathione peroxidase (GPX) protein was significantly reduced in liver, kidney and muscle of GH-treated mice (P < or = 0.03). Likewise, the activity of GPX was decreased in liver and kidney tissues following GH administration (P< or = 0.04). Exogenous GH increased glutathione levels in brain, muscle and liver (P< or = 0.03) compared to saline controls. This evidence, along with previous data, suggests that GH suppresses key components of systems that counter oxidative stress. Reductions in GH and IGF-1 signaling contribute to extended life spans in a variety of species, which may be partially explained by an increased ability to neutralize deleterious byproducts of metabolism.

Animals↗

Evaluation on antagonist activities of polycyclic aromatic hydrocarbons using the yeast two-hybrid detection system for endocrine disruptors.

We constructed an efficient and reliable yeast two-hybrid detection system to evaluate the estrogenic activity of endocrine disruptors (EDs) (Lee et al., Journal of Biochemistry, 131, 2002). This system employs the interaction between the human estrogen receptor beta (hERbeta) ligand binding domain and the co-activator SRC1. The extent of transcriptional activation by those chemicals correlated with estrogenic activities as measured by other assay systems. We applied this assay system to evaluate anti-estrogenic activities and found that known antagonistic compounds, 4-hydroxytamoxifen (OHT) and ICI 182,780, effectively inhibited reporter gene induction by 17beta-estradiol. We then tested the estrogenic and anti-estrogenic activities of polycyclic aromatic hydrocarbons (PAHs) using this assay system. PAHs only weakly induced the lacZ reporter gene at higher concentrations, but clearly showed an inhibitory effect on reporter gene induction by 10(-9) M 17beta-estradiol. These results suggest that PAHs are potentially anti-estrogenic and that the employed yeast detection system could be applicable to primary screening for effectors on estrogen receptor functions.

Endocrine Disruptors↗

Safety aspects of oral antifungal agents.

Four main targets have to be considered when evaluating the safety of new systemically acting, oral antifungals: the liver, the endocrine system, serum cholesterol and the developing embryo. The major endocrine targets for high levels of the antifungal azoles are the adrenal cortex and the gonads. Endocrine studies demonstrate that itraconazole has little potential for interfering with steroid hormones in man. Available data also indicate that itraconazole has low predictable hepatotoxicity potential in man. In rats, serum cholesterol levels are raised during treatment with itraconazole, especially after chronic exposure. This is, however, a species-specific phenomenon which leads to secondary events at toxic doses, especially in long-term toxicity studies. In man, including patients with existing hypercholesterolaemia, serum cholesterol levels are not raised. Ketoconazole has been shown to be teratogenic at high, toxic doses in pregnant rats. The same observation has been made for itraconazole, and it may also be true for fluconazole. However, all three azoles show no teratogenicity in the rabbit. Studies with itraconazole in adrenalectomised rats and in rats given exogenous arachidonic acid indicate that adrenal effects occurring at toxic dose levels are important mediators of teratogenicity. Since itraconazole does not affect adrenal function at levels used to treat infections in man, the teratogenic risk is estimated to be low. Itraconazole is therefore a promising new drug, especially with regard to the assessment of its safety in the liver and endocrine system. Moreover, it is more potent and has a broader antifungal spectrum than other azole antifungals, and its development is considered to be an important step forward in chemotherapy.

Abnormalities, Drug-Induced↗

Vitamin D: more than a "bone-a-fide" hormone.

The vitamin D endocrine system is critical for the proper development and maintenance of mineral ion homeostasis and skeletal integrity. Beyond these classical roles, recent evidence suggests that the bioactive metabolite of vitamin D, 1,25-dihydroxyvitamin D3, functions in diverse physiological processes, such as hair follicle cycling, blood pressure regulation, and mammary gland development. This minireview explores the current progress in unraveling the complexities of the vitamin D endocrine system by focusing on four main areas of research: the resolution of the vitamin D receptor crystal structure, the molecular details of 1,25-dihydroxyvitamin D3-mediated transcription, murine knockout models of key genes in the endocrine system, and alternative vitamin D receptors and ligands.

Animals↗

Endocrine aspects of obesity.

A review is presented of the endocrine status in human obesity. The effect of changes in nutrient intake or body weight and the use of weight-reducing drugs on endocrine systems are discussed. There are several endocrine abnormalities found in obese patients. However, these altered endocrine functions seem secondary to the obese state and do not play a role in the pathogenesis of obesity. Some of these abnormalities are, at least partially, responsible for the development of complications related to the obese state. Weight reduction in general is followed by normalization of endocrine functions. The pharmacological agents used in the treatment of obesity do not influence the endocrine systems significantly.

Gastrointestinal Hormones↗

Psychoneuroendocrinoimmunology: the basis for a novel therapeutic approach in aging.

Along with the nervous and the endocrine systems, the immune system is one of the three major integrative systems in higher organisms. Growing evidence demonstrates an intimate relationship between the immune system and the endocrine and nervous systems: The psychoneuroendocrine system can influence the immune response and thereby the capacity of the organism to cope with illness, and the immune system can have an impact on neuroendocrine function. Such cross-talk among systems is dependent upon feedback loops working to maintain homeostatic equilibrium.

Adrenocorticotropic Hormone↗

The effects of lesions in the lateral septal and hippocampal areas on the humoral immune response of adult female rats.

There are interactions between the immune and the endocrine systems. A major role for adrenal steroids in the modulation of the immune system is well documented and the immune system can apparently activate the adrenal axis at the hypothalamic and/or pituitary level. Sex steroids modify immune function and sex differences in immune function suggest that there are also major interactions between the reproductive system and the immune system. To the extent that the endocrine system is integrated with the immune system, many of the brain areas and neural mechanisms implicated in psychoneuroendocrine processes may be involved in the regulation of psychoneuroimmune processes. We have proposed that the septal region represents an important extrahypothalamic and now propose that the septal region may also represent an important component in the central regulation of psychoneuroimmune processes. We have tested the effects of electrolytic and kainic acid (KA) lesions in the lateral septal area of female rats and have compared the effects of KA lesions in the lateral septal area with KA lesions in the hippocampal region on antibody production following immunization with 100 micrograms ovalbumin in complete Freund's adjuvant. Blood samples were collected on Days 0, 7, 14, 17, and 28 following immunization in the first experiment and on Days 0, 7, 14, and 28 in the second study. All animals were injected again with ovalbumin on Day 14. The IgG, IgA, and IgM antibody titers were then measured by an enzyme-amplified ELISA assay. KA lesions in the lateral septal area produced extensive cell loss in this region and produced a concurrent loss of cell bodies in the CA 3-CA 4 hippocampal areas. Compared to sham and electrolytic septal lesioned rats, KA lesions of the lateral septal area significantly reduced IgG titers on Days 7 and 17 with a trend for Day 14. Similarly, the IgA and IgM titers were significantly lower on Days 7, 14, and 17 for the rats with KA lesions in the lateral septal area. In addition, the KA septal lesioned rats gained more body weight and had higher thymus weights, relative to the electrolytic lesioned and sham groups. In addition, the rats with KA lesions in the hippocampal area showed significantly higher IgM titers on Day 7, elevated IgG titers on Day 14, and lower IgA titers on Day 28, relative to the sham group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Spontaneous growth hormone (GH) secretion by unstimulated human lymphocytes and the effects of GH-releasing hormone and somatostatin.

We investigated in five normal subjects whether the secretion of GH from lymphocytes would occur spontaneously without mitogens and be regulated by GHRH and somatostatin as in the endocrine system. Peripheral blood mononuclear cells were isolated from heparinized blood by the standard Ficoll-Hypaque gradient centrifugation method, and incubated for up to 7 days with or without GHRH, somatostatin analog (SMS 201-995), cycloheximide, or actinomycin D. GH levels in the lyophilized samples were measured by a highly sensitive enzyme immunoassay. GH concentration in culture medium (5 x 10(5) cells/mL) time dependently increased in all subjects, reaching 0.47 +/- 0.18 ng/L at day 7. A protein synthesis inhibitor (cycloheximide) and RNA synthesis inhibitor (actinomycin D) completely blocked GH secretion from lymphocytes. Immunoreactive GH secreted by unstimulated human lymphocytes was similar to pituitary GH in terms of antigenicity and molecular weight. Physiological concentrations of GHRH (10(-10)-10(-8) mol/L) and SMS 201-995 (10(-8)-10(-6) mol/L) had no effects on the spontaneous secretion of GH from human lymphocytes. These results indicate that GH is spontaneously synthesized de novo and secreted from unstimulated human lymphocytes, and that the regulation of GH in the immune system differs from that in the endocrine system.

Adult↗

[Disordered thymus function and endocrine control as one of the bases for the development of a late postradiation immunodeficiency (a review of the literature)].

The review is devoted to the analysis of 155 reference published mainly in the recent years, which deal with the radiation effects on immune, nervous and endocrine systems. The role of thymus in the late manifestations of postradiation immunodeficiency is discussed. The published data on immune system disturbances and postradiation disfunction of endocrine system in the persons who suffered from the Chernobyl accident are considered.

Humans↗

Sleep, cytokines and immune function.

Bi-directional communication pathways exist between the brain and the cytokine-immune-endocrine systems. The hypothalamic-pituitary axis, the efferent neuronal hypothalamus-autonomic nervous system axis, and the direct drainage of macromolecules from the brain into the blood and the lymphatic system provide a network by which the sleeping/waking brain influence bodily functions. Similarly, changes in cytokine levels in the periphery modulate the central nervous system either directly or via the vagal nerve and influence the sleeping/waking brain. In humans, circadian nocturnal sleep-daytime wakefulness is associated with changes in peripheral cytokines, cellular immune functions, and endocrines. Progesterone levels influence sleep and cellular immune functions during the menstrual cycle. The interaction between the circadian sleeping/waking brain and the cytokine-immune-endocrine system are integral to preserving homeostasis. Disorganization or loss of sleep disrupts the harmonious integration of the circadian cytokine-immune-endocrine system. However, the mechanisms of circadian sleep/wakefulness-related cytokine-immune-endocrine functions in host defence against disease remain to be determined.

Journal Article↗

Evolving concepts of the renin-angiotensin system. Focus on renal and vascular mechanisms.

The traditional concept of the renin-angiotensin system (RAS) is a circulation-borne endocrine system, the components of which are secreted by various organs. The product of this biochemical cascade, angiotensin II, acts on specific receptors on multiple target organs. Activation of this circulating system has been shown to result in vasoconstriction and hypertension. In addition to this endocrine system, evidence is emerging that the renin-angiotensin system also exists at multiple local tissue sites. Recent data demonstrating that inhibitors of the RAS are capable of lowering blood pressure in the presence of suppressed as well as elevated plasma renin activity (PRA) have given rise to the hypothesis that these inhibitors exert a large part of their effect on angiotensin that is synthesized by and contained in local tissues. The concept implies that local angiotensin concentrations may exceed those of plasma levels and may play an important role in the tonic control of vascular resistance, cardiac and adrenal functions, and intrarenal events. The hypothesis could explain the broad spectrum of activity of angiotensin-converting enzyme (ACE) inhibitors in hypertensives as well as their continuing antihypertensive activity after plasma ACE levels have been restored.

Animals↗