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1.
Regul Toxicol Pharmacol ; 116: 104688, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32621976

RESUMEN

The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization.


Asunto(s)
Alérgenos/toxicidad , Haptenos/toxicidad , Medición de Riesgo/métodos , Alternativas a las Pruebas en Animales , Animales , Simulación por Computador , Células Dendríticas/efectos de los fármacos , Dermatitis por Contacto/etiología , Humanos , Queratinocitos/efectos de los fármacos , Linfocitos/efectos de los fármacos
2.
J Biochem Mol Toxicol ; 29(3): 129-34, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25358543

RESUMEN

Voltage-gated sodium channels (Na(v)) are essential for initiation and propagation of action potentials. Previous in vitro studies reported that exposure to the Na(v) toxins veratridine and α scorpion toxin cause persistent downregulation of Na(v) mRNA in vitro. However the mechanism of this downregulation is not well characterized. Here, we report that the type-II pyrethroid deltamethrin, which has a similar mechanism as these toxins, elicited an approximate 25% reduction in Na(v) 1.2 and Na(v) 1.3 mRNA in SK-N-AS cells. Deltamethrin-induced decreases of Na(v) mRNA were blocked with the Na(v) antagonist tetrodotoxin, demonstrating a primary role for interaction with Na(v). Pre-treatment with the intracellular calcium chelator BAPTA-AM and the calpain inhibitor PD-150606 also prevented these decreases, identifying a role for intracellular calcium and calpain activation. Because alterations in Na(v) expression and function can result in neurotoxicity, additional studies are warranted to determine whether or not such effects occur in vivo.


Asunto(s)
Calcio/fisiología , Calpaína/fisiología , Insecticidas/farmacología , Canal de Sodio Activado por Voltaje NAV1.2/metabolismo , Canal de Sodio Activado por Voltaje NAV1.3/metabolismo , Nitrilos/farmacología , Piretrinas/farmacología , Línea Celular Tumoral , Regulación hacia Abajo , Humanos , Canal de Sodio Activado por Voltaje NAV1.2/genética , Canal de Sodio Activado por Voltaje NAV1.3/genética , ARN Mensajero/metabolismo
3.
J Neurosci ; 26(52): 13531-6, 2006 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-17192436

RESUMEN

Brain-derived neurotrophic factor (BDNF) is a key regulator of hippocampal synaptic plasticity in the developing and adult nervous system. It can be released from pyramidal neuron dendrites in an activity-dependent manner and has therefore been suggested to serve as a signal that provides the retrograde intercellular communication necessary for Hebbian plasticity and hippocampal-dependent learning. Although much has been learned about BDNF function by field stimulation of hippocampal neurons, it is not known whether moderate action potential-independent depolarization of single cells is capable of releasing sufficient BDNF to influence transmission at individual synapses. In this study, we show directly at the single-cell level that such modulation can occur. By using K-252a, anti-BDNF antibody, and interruption of regulated release, we confirm a model in which postsynaptic depolarization elicits calcium-dependent release of BDNF that diffuses retrogradely and enhances presynaptic transmitter release.


Asunto(s)
Transporte Axonal/fisiología , Factor Neurotrófico Derivado del Encéfalo/fisiología , Hipocampo/citología , Hipocampo/fisiología , Transducción de Señal/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Femenino , Hipocampo/metabolismo , Potenciales de la Membrana/fisiología , Modelos Neurológicos , Embarazo , Terminales Presinápticos/metabolismo , Terminales Presinápticos/fisiología , Terminales Presinápticos/ultraestructura , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/genética , Transmisión Sináptica/fisiología
4.
Neurotoxicology ; 60: 274-279, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27058123

RESUMEN

Pyrethroid insecticide use has increased over recent years because of their low to moderate acute toxicity in mammals. However, there is increasing concern over the potential detrimental effects of pyrethroids on developing animals. Most recently, we have shown that developmental exposure to deltamethrin results in long-term neurobehavioral effects. Pyrethroids exert their toxicity by acting on the voltage-gated sodium channel (Nav), delaying channel inactivation and causing hyperexcitability in the nervous system. Previous in vitro studies found that exposure to agents that increase Na+ influx, including deltamethrin decreased Nav mRNA expression. However, it is unknown whether this occurs in vivo. To determine whether developmental pyrethroid exposure decreases Nav mRNA expression, pregnant mice were exposed to the pyrethroid deltamethrin (0 or 3mg/kg) every three days throughout gestation and lactation. Nav mRNA expression was measured in the striatum and cortex of the offspring at 10-11 months of age, a time at which behavioral abnormalities were still observed. Developmental exposure to deltamethrin decreased expression of Nav mRNA in a region- and isoform-specific fashion by 24-50%. Deltamethrin exposure also resulted in the persistent down-regulation of brain-derived neurotrophic factor (Bdnf) in the striatum by 66% but not in the cortex, suggesting a plausible mechanism for some of the associated behavioral effects observed previously. Taken together these data suggest that developmental deltamethrin exposure results in persistent deficits in Nav and BDNF mRNA expression that may contribute to long-term behavioral deficits.


Asunto(s)
Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Insecticidas/toxicidad , Neuronas/efectos de los fármacos , Nitrilos/toxicidad , Efectos Tardíos de la Exposición Prenatal/metabolismo , Piretrinas/toxicidad , Canales de Sodio Activados por Voltaje/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/metabolismo , Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/metabolismo , Femenino , Masculino , Ratones Endogámicos C57BL , Neuronas/metabolismo , Embarazo , ARN Mensajero/metabolismo
5.
Mol Cell Endocrinol ; 422: 42-56, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26577678

RESUMEN

Ghrelin's receptor, growth hormone secretagogue receptor (GHSR), is highly expressed in the arcuate nucleus (ARC) and in neuropeptide Y (NPY) neurons. Fasting, diet-induced obesity (DIO), and 17ß-estradiol (E2) influence ARC Ghsr expression. It is unknown if these effects occur in NPY neurons. Therefore, we examined the expression of Npy, Agrp, and GHSR signaling pathway genes after fasting, DIO, and E2 replacement in ARC and pools of NPY neurons. In males, fasting increased ARC Ghsr and NPY Foxo1 but decreased NPY Ucp2. In males, DIO decreased ARC and NPY Ghsr and Cpt1c. In fed females, E2 increased Agrp, Ghsr, Cpt1c, and Foxo1 in ARC. In NPY pools, E2 decreased Foxo1 in fed females but increased Foxo1 in fasted females. DIO in females suppressed Agrp and augmented Cpt1c in NPY neurons. In summary, genes involved in GHSR signaling are differentially regulated between the ARC and NPY neurons in a sex-dependent manner.


Asunto(s)
Núcleo Arqueado del Hipotálamo/metabolismo , Estradiol/farmacología , Ayuno/metabolismo , Neuronas/metabolismo , Obesidad/metabolismo , Receptores de Ghrelina/metabolismo , Animales , Femenino , Regulación de la Expresión Génica , Masculino , Ratones , Neuropéptido Y/metabolismo , Obesidad/etiología , Receptores de Ghrelina/genética , Factores Sexuales , Transducción de Señal
7.
Neurotoxicology ; 32(5): 661-5, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21756936

RESUMEN

The "Hot Topic Keynotes: Channelopathies" session of the 26th International Neurotoxicology Conference brought together toxicologists studying interactions of environmental toxicants with ion channels, to review the state of the science of channelopathies and to discuss the potential for interactions between environmental exposures and channelopathies. This session presented an overview of chemicals altering ion channel function and background about different channelopathy models. It then explored the available evidence that individuals with channelopathies may or may not be more sensitive to effects of chemicals.


Asunto(s)
Canalopatías/inducido químicamente , Canalopatías/metabolismo , Exposición a Riesgos Ambientales/efectos adversos , Animales , Congresos como Asunto/tendencias , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inducido químicamente , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Humanos , Activación del Canal Iónico/fisiología
8.
Dev Neurobiol ; 67(13): 1687-98, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17587220

RESUMEN

Neurotrophin activation of Trk receptors elicits diverse effects on neuronal survival, differentiation, and synaptic plasticity. One of the central questions is how specificity is encoded in neurotrophin receptor signaling and actions. A unique downstream protein is the Ankyrin-Repeat Rich Membrane Spanning (ARMS)/Kinase D-interacting substrate-220 kDa (Kidins220), a very abundant scaffold protein in the hippocampus. To determine the roles of ARMS/Kidins220 in hippocampal neurons, we have analyzed the effects of synaptic activity upon the regulation and distribution of ARMS/Kidins220. At early times in vitro (<7 DIV), synaptic activity was low and ARMS/Kidins220 levels were high. As synaptic activity and markers for synapse maturation, such as PSD-95, increased, ARMS/Kidins220 significantly decreased to a plateau by later times in vitro (>12 DIV). Immunocytochemistry showed ARMS/Kidins220 to be concentrated at the tips of growing processes in immature cultures, and more diffusely distributed in older cultures. To examine the apparent inverse relationship between activity and ARMS/Kidins220 levels, neuronal firing was manipulated pharmacologically. Chronic exposure to TTX increased ARMS/Kidins220 levels, whereas bicuculline caused the opposite effect. Moreover, using shRNA to decrease ARMS/Kidins220 levels produced a corresponding increase in synaptic activity. We find that ARMS/Kidins220 may function in neuronal development as an indicator and potentially as a homeostatic regulator of overall synaptic strength in hippocampal neurons.


Asunto(s)
Hipocampo/embriología , Proteínas de la Membrana/metabolismo , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Fosfoproteínas/metabolismo , Sinapsis/metabolismo , Animales , Western Blotting , Hipocampo/citología , Hipocampo/metabolismo , Inmunohistoquímica , Células PC12 , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley
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