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Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through end of lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (in ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display deficient short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, and vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.
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Transtorno Autístico , Retardadores de Chama , Neuropeptídeos , Animais , Feminino , Éteres Difenil Halogenados/toxicidade , Humanos , Exposição Materna/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , FenótipoRESUMO
UCNeuro, a University of California, Riverside student-run organization, developed, implemented, and tested a school-based supplemental science intervention. The purpose of this intervention was to improve students' neuroscience knowledge and education attitudes and meet, in part, California's new elementary science education standards. The intervention consisted of interactive, hands-on neuroscience workshops on the structure of a neuron, neuron-to-neuron communication, brain structure and function, autonomic nervous system function, and drug effects on the brain. Under the supervision of a faculty neuroscientist, undergraduate students implemented the intervention with 77 sixth-grade students in one school in Riverside County, California. Pre- and post-test results showed increases in students' neuroscience knowledge, confidence in achieving their goals, likeliness to go to college, and desire to attend school. Excitement about learning science material and school learning opportunities did not change after the workshops. We hope that the UCNeuro workshops can be employed and adapted to the existing curriculum to improve knowledge in the life sciences while California's new elementary science standards are being operationalized.
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Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that produce neurotoxicity and neuroendocrine disruption. They affect the vasopressinergic system but their disruptive mechanisms are not well understood. Our group reported that rats perinatally exposed to Aroclor-1254 (A1254) and DE-71 (commercial mixtures of PCBs and PBDEs) decrease somatodendritic vasopressin (AVP) release while increasing plasma AVP responses to osmotic activation, potentially emptying AVP reserves required for body-water balance. The aim of this research was to evaluate the effects of perinatal exposure to A1254 or DE-71 (30mgkg/day) on AVP transcription and protein content in the paraventricular and supraoptic hypothalamic nuclei, of male and female rats, by in situ hybridization and immunohistochemistry. cFOS mRNA expression was evaluated in order to determine neuroendocrine cells activation due to osmotic stimulation. Animal groups were: vehicle (control); exposed to either A1254 or DE-71; both, control and exposed, subjected to osmotic challenge. The results confirmed a physiological increase in AVP-immunoreactivity (AVP-IR) and gene expression in response to osmotic challenge as reported elsewhere. In contrast, the exposed groups did not show this response to osmotic activation, they showed significant reduction in AVP-IR neurons, and AVP mRNA expression as compared to the hyperosmotic controls. cFOS mRNA expression increased in A1254 dehydrated groups, suggesting that the AVP-IR decrease was not due to a lack of the response to the osmotic activation. Therefore, A1254 may interfere with the activation of AVP mRNA transcript levels and protein, causing a central dysfunction of vasopressinergic system.
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Arginina Vasopressina/metabolismo , Poluentes Ambientais/toxicidade , Éteres Difenil Halogenados/toxicidade , Células Neuroendócrinas/efeitos dos fármacos , Pressão Osmótica , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , RNA Mensageiro/metabolismo , Núcleo Supraóptico/efeitos dos fármacos , Animais , Arginina Vasopressina/genética , Regulação para Baixo , Feminino , Masculino , Exposição Materna/efeitos adversos , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Gravidez , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , Ratos Sprague-Dawley , Ratos Wistar , Cloreto de Sódio/administração & dosagem , Núcleo Supraóptico/metabolismo , Núcleo Supraóptico/patologia , Transcrição GênicaRESUMO
OBJECTIVE: The purpose of this study was to develop a method for applying calibrated manual massage pressures by using commonly available, inexpensive sphygmomanometer parts and validate the use of this approach as a quantitative method of applying massage therapy to rodents. METHODS: Massage pressures were monitored by using a modified neonatal blood pressure (BP) cuff attached to an aneroid gauge. Lightly anesthetized rats were stroked on the ventral abdomen for 5 minutes at pressures of 20 mm Hg and 40 mm Hg. Blood pressure was monitored noninvasively for 20 minutes following massage therapy at 5-minute intervals. Interexaminer reliability was assessed by applying 20 mm Hg and 40 mm Hg pressures to a digital scale in the presence or absence of the pressure gauge. RESULTS: With the use of this method, we observed good interexaminer reliability, with intraclass coefficients of 0.989 versus 0.624 in blinded controls. In Long-Evans rats, systolic BP dropped by an average of 9.86% ± 0.27% following application of 40 mm Hg massage pressure. Similar effects were seen following 20 mm Hg pressure (6.52% ± 1.7%), although latency to effect was greater than at 40 mm Hg. Sprague-Dawley rats behaved similarly to Long-Evans rats. Low-frequency/high-frequency ratio, a widely-used index of autonomic tone in cardiovascular regulation, showed a significant increase within 5 minutes after 40 mm Hg massage pressure was applied. CONCLUSIONS: The calibrated massage method was shown to be a reproducible method for applying massage pressures in rodents and lowering BP.
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Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Massagem/métodos , Abdome/fisiologia , Animais , Sistema Nervoso Autônomo/fisiologia , Masculino , Modelos Animais , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Esfigmomanômetros , SístoleRESUMO
Introduction: Polybrominated diphenyl ethers (PBDEs) are commercially used flame retardants that bioaccumulate in human tissues, including breast milk. PBDEs produce endocrine and metabolic disruption in experimental animals and have been associated with diabetes and metabolic syndrome (MetS) in humans, however, their sex-specific diabetogenic effects are not completely understood. Our past works show glucolipid dysregulation resulting from perinatal exposure to the commercial penta-mixture of PBDEs, DE-71, in C57BL/6 female mice. Methods: As a comparison, in the current study, the effects of DE-71 on glucose homeostasis in male offspring was examined. C57BL/6N dams were exposed to DE-71 at 0.1 mg/kg/d (L-DE-71), 0.4 mg/kg/d (H-DE-71), or received corn oil vehicle (VEH/CON) for a total of 10 wks, including gestation and lactation and their male offspring were examined in adulthood. Results: Compared to VEH/CON, DE-71 exposure produced hypoglycemia after a 11 h fast (H-DE-71). An increased fast duration from 9 to 11 h resulted in lower blood glucose in both DE-71 exposure groups. In vivo glucose challenge showed marked glucose intolerance (H-DE-71) and incomplete clearance (L- and H-DE-71). Moreover, L-DE-71-exposed mice showed altered glucose responses to exogenous insulin, including incomplete glucose clearance and/or utilization. In addition, L-DE-71 produced elevated levels of plasma glucagon and the incretin, active glucagon-like peptide-1 (7-36) amide (GLP-1) but no changes were detected in insulin. These alterations, which represent criteria used clinically to diagnose diabetes in humans, were accompanied with reduced hepatic glutamate dehydrogenase enzymatic activity, elevated adrenal epinephrine and decreased thermogenic brown adipose tissue (BAT) mass, indicating involvement of several organ system targets of PBDEs. Liver levels of several endocannabinoid species were not altered. Discussion: Our findings demonstrate that chronic, low-level exposure to PBDEs in dams can dysregulate glucose homeostasis and glucoregulatory hormones in their male offspring. Previous findings using female siblings show altered glucose homeostasis that aligned with a contrasting diabetogenic phenotype, while their mothers displayed more subtle glucoregulatory alterations, suggesting that developing organisms are more susceptible to DE-71. We summarize the results of the current work, generated in males, considering previous findings in females. Collectively, these findings offer a comprehensive account of differential effects of environmentally relevant PBDEs on glucose homeostasis and glucoregulatory endocrine dysregulation of developmentally exposed male and female mice.
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Diabetes Mellitus , Retardadores de Chama , Insulinas , Gravidez , Animais , Camundongos , Masculino , Humanos , Feminino , Éteres Difenil Halogenados/toxicidade , Retardadores de Chama/toxicidade , Camundongos Endogâmicos C57BL , GlucoseRESUMO
Pituitary adenylate cyclase-activating polypeptide (PACAP) and the homologous peptide, vasoactive intestinal peptide (VIP), participate in glucose homeostasis using insulinotropic and counterregulatory processes. The role of VIP receptor 2 (VPAC2R) in these opposing actions needs further characterization. In this study, we examined the participation of VPAC2R on basal glycemia, fasted levels of glucoregulatory hormones and on glycemia responses during metabolic and psychogenic stress using gene-deleted (Vipr2-/- ) female mice. The mean basal glycemia was significantly greater in Vipr2-/- in the fed state and after an 8-h overnight fast as compared to wild-type (WT) mice. Insulin tolerance testing following a 5-h fast (morning fast, 0.38 U/kg insulin) indicated no effect of genotype. However, during a more intense metabolic challenge (8 h, ON fast, 0.25 U/kg insulin), Vipr2-/- females displayed significantly impaired insulin hypoglycemia. During immobilization stress, the hyperglycemic response and plasma epinephrine levels were significantly elevated above basal in Vipr2-/- , but not WT mice, in spite of similar stress levels of plasma corticosterone. Together, these results implicate participation of VPAC2R in upregulated counterregulatory processes influenced by enhanced sympathoexcitation. Moreover, the suppression of plasma GLP-1 levels in Vipr2-/- mice may have removed the inhibition on hepatic glucose production and the promotion of glucose disposal by GLP-1. qPCR analysis indicated deregulation of central gene markers of PACAP/VIP signaling in Vipr2-/- , upregulated medulla tyrosine hydroxylase (Th) and downregulated hypothalamic Vip transcripts. These results demonstrate a physiological role for VPAC2R in glucose metabolism, especially during insulin challenge and psychogenic stress, likely involving the participation of sympathoadrenal activity and/or metabolic hormones.
Assuntos
Receptores do Hormônio Hipofisário , Receptores de Peptídeo Intestinal Vasoativo , Camundongos , Feminino , Animais , Receptores de Peptídeo Intestinal Vasoativo/genética , Receptores de Peptídeo Intestinal Vasoativo/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Deleção de Genes , Peptídeo Intestinal Vasoativo/metabolismo , Insulina/metabolismo , Glucose , Peptídeo 1 Semelhante ao Glucagon , Receptores do Hormônio Hipofisário/genética , Receptores Tipo II de Peptídeo Intestinal Vasoativo/genéticaRESUMO
AIMS: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI). METHODS: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin. KEY FINDINGS: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces. SIGNIFICANCE: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI.
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Disfunção Cognitiva/patologia , Disbiose/patologia , Fadiga/patologia , Microbioma Gastrointestinal , Doenças Neuroinflamatórias/patologia , Síndrome do Golfo Pérsico/tratamento farmacológico , Condicionamento Físico Animal , Brometo de Piridostigmina/toxicidade , Animais , Biomarcadores/análise , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/toxicidade , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Disbiose/etiologia , Disbiose/metabolismo , Endotoxemia/etiologia , Endotoxemia/metabolismo , Endotoxemia/patologia , Fadiga/etiologia , Fadiga/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Gliose/etiologia , Gliose/metabolismo , Gliose/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/patologia , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/metabolismo , Brometo de Piridostigmina/administração & dosagemRESUMO
Polybrominated diphenyl ethers (PBDEs) are a class of flame-retardant organohalogen pollutants that act as endocrine/neuroendocrine disrupting chemicals (EDCs). In humans, exposure to brominated flame retardants (BFR) or other environmentally persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and novel organophosphate flame retardants has been associated with increasing trends of diabetes and metabolic disease. However, the effects of PBDEs on metabolic processes and their associated sex-dependent features are poorly understood. The metabolic-disrupting effects of perinatal exposure to industrial penta-PBDE mixture, DE-71, on male and female progeny of C57BL/6N mouse dams were examined in adulthood. Dams were exposed to environmentally relevant doses of PBDEs daily for 10 weeks (p.o.): 0.1 (L-DE-71) and 0.4 mg/kg/d (H-DE-71) and offspring parameters were compared to corn oil vehicle controls (VEH/CON). The following lipid metabolism indices were measured: plasma cholesterol, triglycerides, adiponectin, leptin, and liver lipids. L-DE-71 female offspring were particularly affected, showing hypercholesterolemia, elevated liver lipids and fasting plasma leptin as compared to same-sex VEH/CON, while L- and H-DE-71 male F1 only showed reduced plasma adiponectin. Using the quantitative Folch method, we found that mean liver lipid content was significantly elevated in L-DE-71 female offspring compared to controls. Oil Red O staining revealed fatty liver in female offspring and dams. General measures of adiposity, body weight, white and brown adipose tissue (BAT), and lean and fat mass were weighed or measured using EchoMRI. DE-71 did not produce abnormal adiposity, but decreased BAT depots in L-DE-71 females and males relative to same-sex VEH/CON. To begin to address potential central mechanisms of deregulated lipid metabolism, we used RT-qPCR to quantitate expression of hypothalamic genes in energy-regulating circuits that control lipid homeostasis. Both doses of DE-71 sex-dependently downregulated hypothalamic expression of Lepr, Stat3, Mc4r, Agrp, Gshr in female offspring while H-DE-71 downregulated Npy in exposed females relative to VEH/CON. In contrast, exposed male offspring displayed upregulated Stat3 and Mc4r. Intestinal barrier integrity was measured using FITC-dextran since it can lead to systemic inflammation that leads to liver damage and metabolic disease, but was not affected by DE-71 exposure. These findings indicate that maternal transfer of PBDEs disproportionately endangers female offspring to lipid metabolic reprogramming that may exaggerate risk for adult metabolic disease.
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Disruptores Endócrinos , Poluentes Ambientais , Retardadores de Chama , Bifenilos Policlorados , Animais , Feminino , Masculino , Camundongos , Gravidez , Adiponectina , Proteína Relacionada com Agouti , Colesterol , Óleo de Milho , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , Homeostase , Leptina , Camundongos Endogâmicos C57BL , Organofosfatos , Poluentes Orgânicos Persistentes , Triglicerídeos , Fatores SexuaisRESUMO
The Allan-Herndon Dudley Syndrome (AHDS) is a rare disease caused by the progressive loss of monocarboxylate transporter 8 (MCT8). In patients with AHDS, the absence of MCT8 impairs transport of thyroid hormones (TH) through the blood brain barrier, leading to a central state of TH deficiency. In mice, the AHDS is mimicked by simultaneous deletion of the TH transporters MCT8 and the solute carrier organic anion transporter family member 1c1 (OATP1C1). To support preclinical mouse studies, an analytical methodology was developed and successfully applied for quantifying selected thyroid hormones in mouse whole brain and in specific regions using liquid chromatography tandem mass-spectrometry (LC-MS/MS). An important requirement for the methodology was its high sensitivity since a very low concentration of THs was expected in MCT8/OATP1C1 double-knockout (dko) mouse brain. Seven THs were targeted: L-thyroxine (T4), 3,3´,5-triiodo-L-thyronine-thyronine (T3), 3,3´,5´-triiodo-L-thyronine-thyronine (rT3), 3,3´-diiodo-L-thyronine (3,3´-T2, T2), 3,5-diiodo-L-thyronine (rT2, 3,5-T2), 3-iodo-L-thyronine (T1), 3-iodothyronamine (T1AM). Isotope dilution liquid chromatography triple-quadrupole mass spectrometry methodology was applied for detection and quantification. The method was validated in wild-type animals for mouse whole brain and for five different brain regions (hypothalamus, hippocampus, prefrontal cortex, brainstem and cortex). Instrumental calibration curves ranged from 0.35 to 150 pg/µL with good linearity (r2 >0.996). The limit of quantification was from 0.08 to 0.6 pg/mg, with an intra- and inter-day precision of 4.2-14.02% and 0.4-17.9% respectively, and accuracies between 84.9% and 114.8% when the methodology was validated for the whole brain. In smaller, distinct brain regions, intra- and inter-day precision were 0.6-20.7% and 2.5-15.6% respectively, and accuracies were 80.2-128.6%. The new methodology was highly sensitive and allowed for the following quantification in wild-type mice: (i) for the first time, four distinct thyroid hormones (T4, T3, rT3 and 3,3´-T2) in only approximately 100 mg of mouse brain were detected; (ii) the quantification of T4 and T3 for the first time in distinct mouse brain regions were reported. Further, application of our method to MCT8/OATP1C1 dko mice revealed the expected, relative lack of T3 and T4 uptake into the brain, and confirmed the utility of our analytical method to study TH transport across the blood brain barrier in a preclinical model of central TH deficiency.
Assuntos
Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ânions Orgânicos , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Simportadores/metabolismo , Animais , Encéfalo , Cromatografia Líquida/métodos , Isótopos , Deficiência Intelectual Ligada ao Cromossomo X , Camundongos , Hipotonia Muscular , Atrofia Muscular , Simportadores/genética , Espectrometria de Massas em Tandem/métodos , Hormônios Tireóideos/análise , Tironinas , TiroxinaRESUMO
AIMS: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1]. MAIN METHODS: Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S). KEY FINDINGS: Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair. SIGNIFICANCE: Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.
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Fadiga , Glucose/metabolismo , Deficiências da Aprendizagem , Síndrome do Golfo Pérsico , Brometo de Piridostigmina/efeitos adversos , Animais , Modelos Animais de Doenças , Fadiga/induzido quimicamente , Fadiga/metabolismo , Fadiga/patologia , Humanos , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/patologia , Masculino , Camundongos , Síndrome do Golfo Pérsico/induzido quimicamente , Síndrome do Golfo Pérsico/metabolismo , Síndrome do Golfo Pérsico/patologia , Brometo de Piridostigmina/farmacologiaRESUMO
Organohalogen compounds are global environmental pollutants. They are highly persistent, bioaccumulative, and cause adverse effects in humans and wildlife. Because of the widespread use of these organohalogens in household items and consumer products, indoor contamination may be a significant source of human exposure, especially for children. One significant concern with regard to health effects associated with exposure to organohalogens is endocrine disruption. This review focuses on PCBs and PBDEs as old and new organohalogens, respectively, and their effects on two neuroendocrine systems; thyroid hormones and the arginine vasopressin system (AVP). Regarding neuroendocrine effects of organohalogens, there is considerable information on the thyroid system as a target and evidence is now accumulating that the AVP system and associated functions are also susceptible to disruption. AVP-mediated functions such as osmoregulation, cardiovascular function as well as social behavior, sexual function and learning/memory are discussed. For both thyroid and AVP systems, the timing of exposure seems to play a major role in the outcome of adverse effects. The mechanism of organohalogen action is well understood for the thyroid system. In comparison, this aspect is understudied in the AVP system but some similarities in neural processes, shown to be targeted by these pollutants, serve as promising possibilities for study. One challenge in understanding modes of action within neuroendocrine systems is their complexity stemming, in part, from interdependent levels of organization. Further, because of the interplay between neuroendocrine and neural functions and behavior, further investigation into organohalogen-mediated effects is warranted and may yield insights with wider scope. Indeed, the current literature provides scattered evidence regarding the role of organohalogen-induced neuroendocrine disruption in the neuroplasticity related to both learning functions and brain structure but future studies are needed to establish the role of endocrine disruption in nervous system function and development.
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Arginina Vasopressina/metabolismo , Disruptores Endócrinos/toxicidade , Hidrocarbonetos Halogenados/toxicidade , Plasticidade Neuronal/efeitos dos fármacos , Sistemas Neurossecretores/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Animais , Arginina Vasopressina/análise , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Feminino , Humanos , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos , Síndromes Neurotóxicas/metabolismo , Ratos , Comportamento Social , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/análiseRESUMO
Polybrominated diphenyl ethers (PBDEs) and the structurally similar chemicals polychlorinated biphenyls (PCBs) disrupt the function of multiple endocrine systems. PCBs and PBDEs disrupt the secretion of vasopressin (VP) from the hypothalamus during osmotic activation. Since the peripheral and central vasopressinergic axes are critical for osmotic and cardiovascular regulation, we examined whether perinatal PBDE exposure could impact these functions during physiological activation. Rats were perinatally dosed with a commercial PBDE mixture, DE-71. Dams were given 0 (corn oil control), 1.7 (low dose) or 30.6 mg/kg/day (high dose) in corn oil from gestational day (GD) 6 through postnatal day (PND) 21 by oral gavage. In the male offspring exposed to high dose PBDE plasma thyroxine and triiodothyronine levels were reduced at PND 21 and recovered to control levels by PND 60 when thyroid stimulating hormone levels were elevated. At 14-18 months of age, cardiovascular responses were measured in four groups of rats: Normal (Oil, normosmotic condition), Hyper (Oil, hyperosmotic stress), Hyper PBDE low (1.7 mg/kg/day DE-71 perinatally, hyperosmotic stress), and Hyper PBDE high (30.6 mg/kg/day DE-71 perinatally, hyperosmotic stress). Systolic blood pressure (BP), diastolic BP, and heart rate (HR) were determined using tail cuff sphygmomanometry and normalized to pretreatment values (baseline) measured under basal conditions. Hyperosmotic treatment yielded significant changes in systolic BP in PBDE exposed rats only. Hyper PBDE low and high dose rats showed 36.1 and 64.7% greater systolic BP responses at 3h post hyperosmotic injection relative to pretreatment baseline, respectively. No treatment effects were measured for diastolic BP and HR. Hyper and Hyper PBDE rats showed increased mean plasma osmolality values by 45 min after injection relative to normosmotic controls. In contrast to Hyper rats, Hyper PBDE (high) rats showed a further increase in mean plasma osmolality at 3h (358.3±12.4mOsm/L) relative to 45 min post hyperosmotic injection (325.1±11.4mOsm/L). Impaired osmoregulation in PBDE-treated animals could not be attributed to decreased levels of plasma vasopressin. Our findings suggest that developmental exposure to PBDEs may disrupt cardiovascular reactivity and osmoregulatory responses to physiological activation in late adulthood.
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Éteres Difenil Halogenados/efeitos adversos , Pressão Osmótica/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Long-Evans , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Vasopressinas/sangueRESUMO
Organohalogen compounds such as polychlorinated biphenyls (PCB) and polybrominated diphenyl ethers (PBDE) are global environmental pollutants and highly persistent, bioaccumulative chemicals that produce adverse effects in humans and wildlife. Because of the widespread use of these organohalogens in household items and consumer products, indoor contamination is a significant source of human exposure, especially for children. One significant concern with regard to health effects associated with exposure to organohalogens is endocrine disruption. Toxicological studies on organohalogen pollutants primarily focused on sex steroid and thyroid hormone actions, and findings have largely shaped the way one envisions their disruptive effects occurring. Organohalogens exert additional effects on other systems including other complex endocrine systems that may be disregulated at various levels of organization. Over the last 20 years evidence has mounted in favor of a critical role of nitric oxide (NO) in numerous functions ranging from neuroendocrine functions to learning and memory. With its participation in multiple systems and action at several levels of integration, NO signaling has a pervasive influence on nervous and endocrine functions. Like blockers of NO synthesis, PCBs and PBDEs produce multifaceted effects on physiological systems. Based on this unique set of converging information it is proposed that organohalogen actions occur, in part, by hijacking processes associated with this ubiquitous bioactive molecule. The current review examines the emerging evidence for NO involvement in selected organohalogen actions and includes recent progress from our laboratory that adds to our current understanding of the actions of organohalogens within hypothalamic neuroendocrine circuits. The thyroid, vasopressin, and reproductive systems as well as processes associated with long-term potentiation were selected as sample targets of organohalogens that rely on regulation by NO. Information is provided about other toxicants with demonstrated interference of NO signaling. Our focus on the convergence between NO system and organohalogen toxicity offers a novel approach to understanding endocrine and neuroendocrine disruption that is particularly problematic for developing organisms. This new working model is proposed as a way to encourage future study in elucidating common mechanisms of action that are selected with a better operational understanding of the systems affected.
Assuntos
Disruptores Endócrinos/toxicidade , Éteres Difenil Halogenados/toxicidade , Óxido Nítrico/metabolismo , Bifenilos Policlorados/toxicidade , Animais , Poluentes Ambientais/toxicidade , Humanos , Hidrocarbonetos Halogenados/toxicidade , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Sistemas Neurossecretores/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Polybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucoregulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses revealed fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, decreased thermogenic brown adipose tissue mass, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Other ex vivo glycemic correlates occurred more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and -153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.
Assuntos
Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Endocanabinoides/metabolismo , Éteres Difenil Halogenados/toxicidade , Hormônios/sangue , Fígado/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Glicemia/análise , Diabetes Mellitus/induzido quimicamente , Feminino , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Soybean oil consumption has increased greatly in the past half-century and is linked to obesity and diabetes. To test the hypothesis that soybean oil diet alters hypothalamic gene expression in conjunction with metabolic phenotype, we performed RNA sequencing analysis using male mice fed isocaloric, high-fat diets based on conventional soybean oil (high in linoleic acid, LA), a genetically modified, low-LA soybean oil (Plenish), and coconut oil (high in saturated fat, containing no LA). The 2 soybean oil diets had similar but nonidentical effects on the hypothalamic transcriptome, whereas the coconut oil diet had a negligible effect compared to a low-fat control diet. Dysregulated genes were associated with inflammation, neuroendocrine, neurochemical, and insulin signaling. Oxt was the only gene with metabolic, inflammation, and neurological relevance upregulated by both soybean oil diets compared to both control diets. Oxytocin immunoreactivity in the supraoptic and paraventricular nuclei of the hypothalamus was reduced, whereas plasma oxytocin and hypothalamic Oxt were increased. These central and peripheral effects of soybean oil diets were correlated with glucose intolerance but not body weight. Alterations in hypothalamic Oxt and plasma oxytocin were not observed in the coconut oil diet enriched in stigmasterol, a phytosterol found in soybean oil. We postulate that neither stigmasterol nor LA is responsible for effects of soybean oil diets on oxytocin and that Oxt messenger RNA levels could be associated with the diabetic state. Given the ubiquitous presence of soybean oil in the American diet, its observed effects on hypothalamic gene expression could have important public health ramifications.
Assuntos
Diabetes Mellitus/etiologia , Expressão Gênica/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Ocitocina/sangue , Óleo de Soja/efeitos adversos , Animais , Inflamação/etiologia , Ácido Linoleico/efeitos adversos , Masculino , Camundongos , Doenças do Sistema Nervoso/etiologia , Obesidade/etiologia , Estigmasterol/efeitos adversosRESUMO
Flavin-containing monooxigenases (FMOs) are a polymorphic family of drug and pesticide metabolizing enzymes, found in the smooth endoplasmatic reticulum that catalyze the oxidation of soft nucleophilic heteroatom substances to their respective oxides. Previous studies in euryhaline fishes have indicated induction of FMO expression and activity in vivo under hyperosmotic conditions. In this study we evaluated the effect of hypersaline conditions in rat kidney. Male Sprague-Dawley rats were injected intraperitoneal with 3.5M NaCl at a doses ranging from 0.3cm(3)/100g to 0.6cm(3)/100g in two separate treatments. Three hours after injection, FMO activities and FMO1 protein was examined in the first experiment, and the expression of FMO1 mRNA was measured in the second experiment from kidneys after treatment with NaCl. A positive significant correlation was found between FMO1 protein expression and plasma osmolarity (p<0.05, r=0.6193). Methyl-p-tolyl sulfide oxidase showed a statistically significant increase in FMO activity, and a positive correlation was observed between plasma osmolarity and production of FMO1-derived (R)-methyl-p-tolyl sulfoxide (p<0.05, r=0.6736). Expression of FMO1 mRNA was also positively correlated with plasma osmolality (p<0.05, r=0.8428). Similar to studies in fish, these results suggest that expression and activities of FMOs may be influenced by hyperosmotic conditions in the kidney of rats.
Assuntos
Rim/enzimologia , Oxigenases/metabolismo , Animais , Western Blotting , Masculino , Concentração Osmolar , Oxigenases/biossíntese , Oxigenases/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Cloreto de Sódio/administração & dosagem , Estatísticas não ParamétricasRESUMO
Magnetic resonance imaging (MRI) is increasingly used in the assessment of the severity and progression of neurotrauma. We evaluated temporal and regional changes after mild fluid percussion (FPI) and controlled cortical impact (CCI) injury using T2-weighted-imaging (T2WI) and diffusion-weighted imaging (DWI) MRI over 7 days. Region of interest analysis of brain areas distant to the injury site (such as the hippocampus, retrosplenial and piriform cortices, and the thalamus) was undertaken. In the hippocampus of CCI animals, we found a slow increase (51%) in apparent diffusion coefficients (ADC) over 72 h, which returned to control values. The hippocampal T2 values in the CCI animals were elevated by 18% over the 7-day time course compared to control, indicative of edema formation. Histological analysis supported the lack of overt cellular loss in most brain regions after mild CCI injury. FPI animals showed a generalized decrease in hippocampal ADC values over the first 72 h, which then returned to sham levels, with decreased T2 values over the same period, which remained depressed at 7 days. Histological assessment of FPI animals revealed numerous shrunken cells in the hippocampus and thalamus, but other regions showed little damage. Increased immunohistochemical staining for microglia and astroglia at 7 days post-injury was greater in FPI animals within the affected brain regions. In summary, traumatic brain injury is less severe in mild CCI than FPI, based on the temporal events assessed with MRI.
Assuntos
Lesões Encefálicas/patologia , Encéfalo/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Animais , Astrócitos/patologia , Biomarcadores/metabolismo , Encéfalo/fisiopatologia , Lesões Encefálicas/fisiopatologia , Difusão , Modelos Animais de Doenças , Progressão da Doença , Gliose/etiologia , Gliose/patologia , Gliose/fisiopatologia , Hipocampo/lesões , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Microglia/patologia , Degeneração Neural/etiologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Tálamo/patologia , Tálamo/fisiopatologiaRESUMO
The neuropeptide, vasopressin (VP) is synthesized in magnocellular neuroendocrine cells (MNCs) located within the supraoptic (SON) and paraventricular (PVN) nuclei of the mammalian hypothalamus. VP has multiple functions including maintenance of body fluid homeostasis, cardiovascular control, learning and memory, and nervous system development. Polybrominated diphenyl ethers (PBDEs), used as additive flame retardants, have been shown to interfere with hormone metabolism and function. Previously, we demonstrated that the technical polychlorinated biphenyl (PCB) mixture, Aroclor 1254, inhibits somatodendritic VP release from the SON of osmotically stimulated rats. The objectives of the current study were to test whether PBDEs affect central VP release in a similar manner and to determine the potency of several PCB and PBDE congeners in order to identify a common mode of action for these persistent chemicals. The current work shows that the commercial PBDE mixture (DE-71) significantly decreased somatodendritic VP release from rat SON punches in a strain-independent manner. In addition, the specific congeners PBDE 47 and PCB 47 (15 and 5 microM) were also neuroactive in this system. To explore structure/activity relationships, we compared the effects of PBDE 77 with PCB 77. PBDE 77, but not PCB 77 significantly reduced VP release. These results show that like PCBs, PBDEs perturb signaling mechanisms responsible for hormone release, and that environmentally relevant PBDE congeners are more neuroactive than the commercial mixtures with noncoplanarity of these compounds playing a role in promoting neuroactivity.
Assuntos
Disruptores Endócrinos/toxicidade , Sistemas Neurossecretores/efeitos dos fármacos , Bifenil Polibromatos/toxicidade , Bifenilos Policlorados/toxicidade , Vasopressinas/metabolismo , Animais , Biotransformação/efeitos dos fármacos , Éteres Difenil Halogenados , Masculino , Concentração Osmolar , Éteres Fenílicos/toxicidade , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
The increasing occurrence of poisoning accidents in marine animals caused by the amnesic shellfish toxin, domoic acid (DOM), necessitates a better understanding of the factors contributing to DOM neurotoxicity. Here we evaluated the contribution and temporal involvement of NMDA, non-NMDA- and metabotropic-type glutamate receptors (GluRs) in DOM-induced neuronal death using rat primary mixed cortical cultures. Co-application of antagonists for AMPA/kainate- (NBQX) and NMDA-type GluRs (D-AP5) but not for metabotropic GluRs reduced DOM toxicity induced by either of three EC50 dose/duration exposure paradigms. Maximal protection offered by D-AP5 and NBQX either extended or not to the 30- to 60-min period after DOM exposure, respectively. Antagonists were ineffective if applied with a 2-h delay, indicating the presence of a critical time window for neuronal protection after DOM exposure. Early effects correlated with neuronal swelling was seen as early as 10 min post-DOM, which has been linked to non-NMDAR-mediated depolarization and release of endogenous glutamate. That DOM toxicity is dictated by iGluRs is supported by the finding that increased efficacy and potency of DOM with in vitro neuronal maturation are positively correlated with elevated protein levels of iGluR subunits, including NR1, GluR1, GluR2/3, GluR5, and GluR6/7. We determined the time course of DOM excitotoxicity. At >10 microM maximal neuronal death occurs within 2 h, while doses < or = 10 microM continue to produce death during the subsequent 22-h washout period, indicating a quicker progression of the neuronal death cascade with high DOM concentrations. Accordingly, NBQX applied 30 min post-DOM afforded better protection against low dose/prolonged duration (3 microM/24 h) than against high dose/brief duration exposure (50 microM/10 min). Interestingly, prior exposure to subthreshold DOM dose-dependently aggravated toxicity produced by a subsequent exposure to DOM. These findings provide greater insight into the complex properties underlying DOM toxicity, including the sequential involvement of multiple GluRs, greater potency with increasing neuronal maturation and protein levels of iGluRs, varying efficacy depending on dose, duration, and prior history of DOM exposure.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/metabolismo , Ácido Caínico/análogos & derivados , Toxinas Marinhas/toxicidade , Neurotoxinas/toxicidade , Receptores de Glutamato/metabolismo , Animais , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feto/citologia , Imunoquímica , Ácido Caínico/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato/classificaçãoRESUMO
The phytoplankton-derived neurotoxin, domoic acid (DOM), frequently causes poisoning of marine animals and poses an increasing threat to public health through contamination of seafood. In this study, we used stereotactic microinjection technique to administer varying amounts of DOM into the hippocampal CA1 region in order to examine potential histopathological changes after injection of sub-lethal concentrations to CA1 pyramidal neurons. Gross anatomical abnormalities in CA1 were observed at above 10 microM DOM (3 pmol in 0.3 microl saline). At 1mM concentration, DOM produces both ipsilateral and contralateral neuronal cell death in CA1, CA3 as well as dentate gyrus subfields. Animal behavioral changes after microinjection were similar to those observed by previous studies through systemic DOM injection. Neuronal degeneration was paralleled by reduced glutamate receptor (NR1, GluR1 and GluR6/7) immunolabeling throughout the whole hippocampal formation. Pre-injection of the AMPA/KA receptor antagonist NBQX (10 microM, 0.3 microl) blocked 1mM DOM-induced neuronal degeneration as well as behavioral symptoms. At concentrations lower than 10 microM, no histopathological changes were observed microscopically, nor were the levels of immunostaining of NR1, GluR1, GluR6/7 different. However, increased immunolabeling of autophosphorylated calcium-calmodulin-dependent kinase II (CaMKII, p-Thr286) and phosphorylated cAMP response element binding protein (CREB, p-Ser133) were observed at 24 h post-injection, suggesting that altered intracellular signal transduction mediated by GluRs might be an adaptive cellular protective mechanism against DOM-induced neurotoxicity.