Myelotoxicity in genistein-, nonylphenol-, methoxychlor-, vinclozolin- or ethinyl estradiol-exposed F-1 generations of Sprague-Dawley rats following developmental and adult exposures
ABSTRACT The myelotoxicity of five endocrine active chemicals was evaluated in F1 generation of Sprague-Dawley rats following developmental and adult exposures at three concentration levels. Rats were exposed to genistein (GEN: 25, 250 and 1250 ppm), nonylphenol (NPH: 25, 500 and 2000 ppm), methoxychlor (MXC: 10, 100 and 1000 ppm), vinclozolin (VCZ: 10, 150 and 750 ppm) and ethinyl estradiol (EE2: 5, 25 and 200 ppb) gestationally and lactationally through dams from day 7 of gestation and through feed after weaning on postnatal day (PND) 22 to PND 64. The parameters examined included the number of recovered bone marrow cells, DNA synthesis, and colony forming units (CFU) in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and erythropoietin. Except for the EE2, the concentrations of other individual chemicals in the diet were in an approximate range that allowed for a comparison to be made in terms of myelotoxic potency. Decreases in the DNA synthesis, CFU-GM and CFU-M seemed to be the common findings among the alterations induced by these compounds. Using the numbers of alterations induced by each chemical in the parameters examined as criteria for comparison, the order of myelotoxic potency in F(1) males was: GEN>MXC>NPH>VCZ; the order in females: GEN>NPH>VCZ. Additionally, some of the functional changes induced by these compounds were gender-specific or dimorphic. Overall, the results demonstrated that developmental and adult exposures of F1 rats to these endocrine active chemicals at the concentrations tested had varied degrees of myelotoxicity with GEN being the most potent. Furthermore, the sex-specific effects of these chemicals in F1 male and female rats suggest that there may be interactions between these compounds and sex hormone in modulating these responses.
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- "This suggests that Epo has a gender preference with neonatal benefit in females, whose mechanisms must be further investigated. Together with other studies demonstrating that gender similarly affects injury models (53, 54), these studies suggest that gender should be carefully considered in experimental HIE. "
ABSTRACT: Treatments for neonatal hypoxic-ischemic encephalopathy (HIE) have been limited. The aim of this paper is to offer translational research guidance on stem cell therapy for neonatal HIE by examining clinically relevant animal models, practical stem cell sources, safety and efficacy of endpoint assays, as well as a general understanding of modes of action of this cellular therapy. In order to do so, we discuss the clinical manifestations of HIE, highlighting its overlapping pathologies with stroke and providing insights on the potential of cell therapy currently investigated in stroke, for HIE. To this end, we draw guidance from recommendations outlined in stem cell therapeutics as an emerging paradigm for stroke or STEPS, which have been recently modified to Baby STEPS to cater for the "neonatal" symptoms of HIE. These guidelines recognized that neonatal HIE exhibit distinct disease symptoms from adult stroke in need of an innovative translational approach that facilitates the entry of cell therapy in the clinic. Finally, new information about recent clinical trials and insights into combination therapy are provided with the vision that stem cell therapy may benefit from available treatments, such as hypothermia, already being tested in children diagnosed with HIE.Frontiers in Neurology 08/2014; 5:147. DOI:10.3389/fneur.2014.00147
- "j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y ta a p al., 2005), obesity (Ruhlen et al., 2008), alteration of thymic functions (Yellayi et al., 2002), myelotoxicity (Guo et al., 2005) and alterations in the sexually dimorphic behavior (Flynn et al., 2000). "
Article: Toxicology and Applied Pharmacology[Show abstract] [Hide abstract]
ABSTRACT: Because of the complexity of estrogen receptor (ER) physiological activity, the interaction of pure isoflavones or soy-based diets on ER needs to be clearly demonstrated. To investigate the effects of the administration of isoflavones as a pure compound or as a component of diet on the ER transcriptional activity in adult mice. Effects of acute (6 h) and chronic (21 days) oral administration of soy milk, pure genistein and a mix of genistein and daidzein was studied in living ERE-Luc mice. In this animal model, the synthesis of luciferase is under the state of ER transcriptional activity. Luciferase activity was measured in living mice by daily bioluminescence imaging sessions and in tissue extracts by enzymatic assay. Acute, oral administration of genistein or soymilk caused a significant increase of ER activity in liver. In a 20 day long treatment, soymilk was more potent than genistein in liver and appeared to extend its influence on ER transcriptional activity in other tissues, such as the digestive tract. A mixture of pure genistein and daidzein at the same concentration as in soymilk failed to induce significant changes during acute and chronic studies suggesting an important, uncharacterized role of the soymilk matrix. Consistent with this observation, synergistic effects of the matrix plus isoflavones were observed in MCF-7 cells stably transfected with the ERE-luc construct. This study underlines the limitations of the analysis of single food components in the evaluation of their effects on estrogen receptor activity and advocates the necessity to use complex organisms for the full comprehension of the effects of compounds altering the endocrine balance.Toxicology and Applied Pharmacology 05/2009; 237(3):288-97. DOI:10.1016/j.taap.2009.03.022 · 3.71 Impact Factor
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- "High concentrations of genistein have been shown to cause apoptosis and necrosis in testis cells (Kumi-Diaka et al. 1999), primary cortical neuron cultures from Spraugue-Dawley rats (Linford et al. 2001), human thymocytes (McCabe and Orrenius 1993), and human lymphoblastoid cells (Morris et al. 1998). In addition, in vivo studies showed that genistein causes developmental and growth toxicity, myelotoxicity , and brain apoptosis (Choi and Lee 2004; Ingham et al. 2004; Guo et al. 2005). Estrogen replacement therapy (ERT) is widely used to treat diseases such as Alzheimer's disease, osteoporosis, and cardiovascular disease, that are caused by low levels of estrogen (Kuller 1996; Spritzerm and Wender 2007). "
ABSTRACT: Genistein is a phytoestrogen found at a high level in soybeans. In vitro and in vivo studies showed that high concentrations of genistein caused toxic effects. This study was designed to test the feasibility of zebrafish embryos for evaluating developmental toxicity and estrogenic potential of high genistein concentrations. The zebrafish embryos at 24 h post-fertilization were exposed to genistein (1 x 10(-4) M, 0.5 x 10(-4) M, 0.25 x 10(-4) M) or vehicle (ethanol, 0.1%) for 60 h. Genistein-treated embryos showed decreased heart rates, retarded hatching times, decreased body length, and increased mortality in a dose-dependent manner. After 0.25 x 10(-4) M genistein treatment, malformations of survived embryos such as pericardial edema, yolk sac edema, and spinal kyphosis were also observed. TUNEL assay results showed apoptotic DNA fragments in brain. This study also confirmed the estrogenic potential of genistein by EGFP expression in the brain of the mosaic reporter zebrafish embryos. This study first demonstrated that high concentrations of genistein caused a teratogenic effect on zebrafish embryos and confirmed the estrogenic potential of genistein in mosaic reporter zebrafish embryos.Toxicology mechanisms and methods 03/2009; 19(3):251-6. DOI:10.1080/15376510802563330 · 1.52 Impact Factor