RESUMEN

AIMS: The study examined that morin as possible antioxidant and neuroprotective due to oxidative stress (H2O2) in zebrafish larval model. MATERIALS AND METHODS: Zebrafish larvae were induced with oxidative stress using H2O2 at 1 mM; their behavioural changes were assessed through partition preference and horizontal compartment test. The head section without eyes and yolk sac of zebrafish larvae were employed for enzyme assays such as SOD, CAT, Thiobarbituric acid reactive substances assay, reduced glutathione, glutathione peroxidase activity, glutathione S transferase, Acetylcholinesterase activity and nitrate levels. Also, intracellular ROS and apoptosis in larval head was detected by DCFDA and acridine orange staining followed by gene expression studies. KEY FINDINGS: Morin exposure was not harmful to the larvae at concentration between 20 and 60 µM, but it caused non-lethal deformity between 80 and 100 µM. In the partition test, zebrafish embryos treated with H2O2 showed cognitive impairment, whereas the morin-treated groups showed an improved behavioural activity. The study also found that restoring antioxidant enzymes and reduced lipid peroxidation which had a neuroprotective impact. Inhibition of NO overproduction and increased AChE activity were also shown to reduce the neuronal damage. Apoptosis and intracellular ROS levels were reduced in larvae when it was co-incubated with morin. Morin treatment up regulated the antioxidant enzymes against oxidative stress. SIGNIFICANCE: Morin provides protection against H2O2 induced oxidative stress through a cellular antioxidant defence mechanism by up-regulating gene expression, thus increasing the antioxidant activity at cellular or organismal stage.

Asunto(s)

Antioxidantes/farmacología , Embrión no Mamífero/metabolismo , Flavonoides/farmacología , Síndromes de Neurotoxicidad , Estrés Oxidativo/efectos de los fármacos , Pez Cebra/embriología , Animales , Embrión no Mamífero/patología , Peróxido de Hidrógeno/efectos adversos , Peróxido de Hidrógeno/farmacología , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/patología

RESUMEN

There is a worldwide concern on adverse health effects of dietary exposure to acrylamide (AA) due to its presence in commonly consumed foods. AA is formed when carbohydrate rich foods containing asparagine and reducing sugars are prepared at high temperatures and low moisture conditions. Upon oral intake, AA is rapidly absorbed and distributed to all organs. AA is a known human neurotoxicant that can reach the developing foetus via placental transfer and breast milk. Although adverse neurodevelopmental effects have been observed after prenatal AA exposure in rodents, adverse effects of AA on the developing brain has so far not been studied in humans. However, epidemiological studies indicate that gestational exposure to AA impair foetal growth and AA exposure has been associated with reduced head circumference of the neonate. Thus, there is an urgent need for further research to elucidate whether pre- and perinatal AA exposure in humans might impair neurodevelopment and adversely affect neuronal function postnatally. Here, we review the literature with emphasis on the identification of critical knowledge gaps in relation to neurodevelopmental toxicity of AA and its mode of action and we suggest research strategies to close these gaps to better protect the unborn child.

Asunto(s)

Acrilamida/toxicidad , Exposición Dietética/efectos adversos , Síndromes de Neurotoxicidad/embriología , Acrilamida/farmacocinética , Animales , Desarrollo Embrionario/efectos de los fármacos , Femenino , Manipulación de Alimentos , Humanos , Intercambio Materno-Fetal , Embarazo

RESUMEN

A literature review and health effects evaluation were conducted for n-butanol, a chemical that occurs naturally in some foods, which is an intermediate in the production of butyl esters and can be used as a gasoline additive or blend. Studies evaluating n-butyl acetate were included in the review as n-butyl acetate is rapidly converted to n-butanol following multiple routes of exposure. The primary n-butanol health effects identified were developmental and nervous system endpoints. In conducting the literature review and evaluating study findings, the following observations were made: (1) developmental findings were consistently identified; (2) neurodevelopmental findings were inconsistent; (3) evidence for nervous system effects was weak; (4) comparing internal doses from oral and inhalation exposures using physiologically based pharmacokinetic models introduces uncertainties; and (5) a lack of mechanistic information for n-butanol resulted in the reliance on mechanistic data for ethanol, which may or may not be applicable to n-butanol. This paper presents findings from a literature review on the health effects of n-butanol and proposes research to help reduce uncertainty that exists due to database limitations.

Asunto(s)

1-Butanol/toxicidad , Acetatos/toxicidad , Contaminantes Ambientales/toxicidad , Sistema Nervioso/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Pruebas de Toxicidad , 1-Butanol/farmacocinética , Acetatos/farmacocinética , Animales , Desarrollo Embrionario/efectos de los fármacos , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/farmacocinética , Femenino , Humanos , Sistema Nervioso/crecimiento & desarrollo , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Medición de Riesgo , Toxicocinética

RESUMEN

Diagnostic and invasive procedures in premature infants may require general anesthesia. General anesthetics interfere with the development of the immature animal brain. Accelerated apoptosis, disturbed synaptogenesis, and cytoarchitecture are among the mechanisms suspected to underlie this phenomenon. The implications for humans are unknown. This article presents current suspected mechanisms of anesthesia-induced neurotoxicity and elaborates on the difficulties in translating results from animal research to human. Ethical considerations limit the conduct of such experiments in human neonates, but the use of animal models is still considered feasible. Vulnerable periods in brain development need further identification as do neurotoxic and neuroprotective interventions.

Asunto(s)

Anestesia General/efectos adversos , Anestésicos Generales/farmacología , Encéfalo/efectos de los fármacos , Síndromes de Neurotoxicidad/fisiopatología , Anestésicos Generales/efectos adversos , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Epigénesis Genética/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Neonatología , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/etiología , Perinatología , Investigación Biomédica Traslacional

RESUMEN

In 2017, the US Food and Drug Administration warned that exposure to anesthetic medicines for lengthy periods of time or over multiple surgeries may affect brain development in children aged less than 3 years. Since then, the clinical literature continues to find mixed evidence of pediatric anesthesia-related neurotoxicity. However, several new human studies provide strong evidence that a single short exposure to general anesthesia in young children does not cause detectable neurocognitive injury by neuropsychological testing. These newer findings are reassuring, but cannot be extrapolated to children who are deemed to be at highest risk of neurologic injury after anesthesia.

Asunto(s)

Anestesia General/efectos adversos , Anestésicos Generales/efectos adversos , Encéfalo/crecimiento & desarrollo , Desarrollo Infantil , Síndromes de Neurotoxicidad/etiología , Encéfalo/embriología , Preescolar , Humanos , Lactante , Recién Nacido , Pruebas de Inteligencia , Pruebas de Estado Mental y Demencia , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/fisiopatología , Estados Unidos , United States Food and Drug Administration

RESUMEN

Conventional in vitro toxicity studies have focused on identifying IC50 and the underlying mechanisms, but how toxicants influence biophysical and biomechanical changes in human cells, especially during developmental stages, remain understudied. Here, using an atomic force microscope, we characterized changes in biophysical (cell area, actin organization) and biomechanical (Young's modulus, force of adhesion, tether force, membrane tension, tether radius) aspects of human fetal brain-derived neural progenitor cells (NPCs) induced by four classes of widely used toxic compounds, including rotenone, digoxin, N-arachidonoylethanolamide (AEA), and chlorpyrifos, under exposure up to 36 h. The sub-cellular mechanisms (apoptosis, mitochondria membrane potential, DNA damage, glutathione levels) by which these toxicants induced biochemical changes in NPCs were assessed. Results suggest a significant compromise in cell viability with increasing toxicant concentration (p < 0.01), and biophysical and biomechanical characteristics with increasing exposure time (p < 0.01) as well as toxicant concentration (p < 0.01). Impairment of mitochondrial membrane potential appears to be the most sensitive mechanism of neurotoxicity for rotenone, AEA and chlorpyrifos exposure, but compromise in plasma membrane integrity for digoxin exposure. The surviving NPCs remarkably retained stemness (SOX2 expression) even at high toxicant concentrations. A negative linear correlation (R2 = 0.92) exists between the elastic modulus of surviving cells and the number of living cells in that environment. We propose that even subtle compromise in cell mechanics could serve as a crucial marker of developmental neurotoxicity (mechanotoxicology) and therefore should be included as part of toxicology assessment repertoire to characterize as well as predict developmental outcomes.

Asunto(s)

Apoptosis/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Ácidos Araquidónicos/administración & dosificación , Ácidos Araquidónicos/toxicidad , Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Daño del ADN/efectos de los fármacos , Digoxina/administración & dosificación , Digoxina/toxicidad , Relación Dosis-Respuesta a Droga , Endocannabinoides/administración & dosificación , Endocannabinoides/toxicidad , Humanos , Insecticidas/administración & dosificación , Insecticidas/toxicidad , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Células-Madre Neurales/patología , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/patología , Alcamidas Poliinsaturadas/administración & dosificación , Alcamidas Poliinsaturadas/toxicidad

RESUMEN

Detection of developmental neurotoxicity (DNT) has been recognized as a major challenge by regulatory bodies and science. In search of sensitive and specific test methods, spontaneous tail coiling of embryonic zebrafish has been recommended as a promising tool for identification of DNT-inducing chemicals. The present study was designed to develop a protocol for a prolonged test to study neurotoxicity during the entire development of coiling movement in zebrafish embryos. Ambient illumination was found to modulate coiling activity from the very onset of tail movements representing the earliest behavioral response to light possible in zebrafish. In the dark, embryos displayed increased coiling activity in a way known from photokinesis, a stereotypical element of the visual motor response. Elevated coiling activity during dark phases allows for the development of test strategies that integrate later coiling movements under the control of a further developed nervous system. Furthermore, zebrafish embryos were exposed to ethanol, and coiling activity was analyzed according to the new test protocol. Exposure of embryos to non-teratogenic concentrations of ethanol (0.4-1%) resulted in a delay of the onset of coiling activity and heartbeat. Moreover, ethanol produced a dose-dependent increase in coiling frequency at 26 h post-fertilization, indicating the involvement of neurotoxic mechanisms. Analysis of coiling activity during prolonged exposure allowed for (1) attributing effects on coiling activity to different mechanisms and (2) preventing false interpretation of results. Further research is needed to verify the potential of this test protocol to distinguish between different mechanisms of neurotoxicity.

Asunto(s)

Embrión no Mamífero/efectos de los fármacos , Etanol/toxicidad , Síndromes de Neurotoxicidad/etiología , Animales , Etanol/farmacología , Síndromes de Neurotoxicidad/embriología , Desempeño Psicomotor/efectos de los fármacos , Cola (estructura animal)/fisiopatología , Pez Cebra/embriología , Pez Cebra/crecimiento & desarrollo

RESUMEN

Methylmercury (MeHg) is a toxic chemical compound naturally produced mainly in the aquatic environment through the methylation of inorganic mercury catalyzed by aquatic microorganisms. MeHg is biomagnified in the aquatic food chain and, consequently, piscivorous fish at the top of the food chain possess huge amounts of MeHg (at the ppm level). Some populations that have fish as main protein's source can be exposed to exceedingly high levels of MeHg and develop signs of toxicity. MeHg is toxic to several organs, but the central nervous system (CNS) represents a preferential target, especially during development (prenatal and early postnatal periods). Though the biochemical events involved in MeHg-(neuro)toxicity are not yet entirely comprehended, a vast literature indicates that its pro-oxidative properties explain, at least partially, several of its neurotoxic effects. As result of its electrophilicity, MeHg interacts with (and oxidize) nucleophilic groups, such as thiols and selenols, present in proteins or low-molecular weight molecules. It is noteworthy that such interactions modify the redox state of these groups and, therefore, lead to oxidative stress and impaired function of several molecules, culminating in neurotoxicity. Among these molecules, glutathione (GSH; a major thiol antioxidant) and thiol- or selenol-containing enzymes belonging to the GSH antioxidant system represent key molecular targets involved in MeHg-neurotoxicity. In this review, we firstly present a general overview concerning the neurotoxicity of MeHg. Then, we present fundamental aspects of the GSH-antioxidant system, as well as the effects of MeHg on this system.

Asunto(s)

Antioxidantes/metabolismo , Glutatión/metabolismo , Compuestos de Metilmercurio , Síndromes de Neurotoxicidad , Neurotoxinas , Estrés Oxidativo/efectos de los fármacos , Animales , Humanos , Compuestos de Metilmercurio/farmacocinética , Compuestos de Metilmercurio/toxicidad , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/metabolismo , Neurotoxinas/farmacocinética , Neurotoxinas/toxicidad

RESUMEN

While Δ9-tetrahydrocannabinol (THC) has been widely studied in the realm of developmental and reproductive toxicology, few studies have investigated potential toxicities from a second widely used cannabis constituent, cannabidiol (CBD). CBD is popularized for its therapeutic potential for reducing seizure frequencies in epilepsy. This study investigated developmental origins of health and disease (DOHaD) via multigenerational gene expression patterns, behavior phenotypes, and reproductive fitness of a subsequent F1 following an F0 developmental exposure of zebrafish (Danio rerio) to THC (0.024, 0.12, 0.6 mg/L; 0.08, 0.4, 2 µM) or CBD (0.006, 0.03, 0.15 mg/L; 0.02, 0.1, 0.5 µM). Embryonic exposure at these concentrations did not cause notable morphological abnormalities in either F0 or F1 generations. However, during key developmental stages (14, 24, 48, 72, and 96 h post fertilization) THC and CBD caused differential expression of c-fos, brain-derived neurotrophic factor (bdnf), and deleted-in-azoospermia like (dazl), while in F1 larvae only CBD differentially expressed dazl. Larval photomotor behavior was reduced (F0) or increased (F1) by THC exposure, while CBD had no effect on F0 larvae, but decreased activity in the unexposed F1 larvae. These results support our hypothesis of cannabinoid-related developmental neurotoxicity. As adults, F0 fecundity was reduced, but it was not in F1 adults. Conversely, in the adult open field test there were no significant effects in F0 fish, but a significant reduction in the time in periphery was seen in F1 fish from the highest THC exposure group. The results highlight the need to consider long-term ramifications of early-life exposure to cannabinoids.

Asunto(s)

Encéfalo/efectos de los fármacos , Cannabidiol/toxicidad , Dronabinol/toxicidad , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Síndromes de Neurotoxicidad/genética , Pez Cebra/genética , Factores de Edad , Animales , Animales Modificados Genéticamente , Conducta Animal/efectos de los fármacos , Encéfalo/embriología , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Fertilidad/efectos de los fármacos , Fertilidad/genética , Actividad Motora/efectos de los fármacos , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Medición de Riesgo , Pez Cebra/embriología , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo

Asunto(s)

Encéfalo/efectos de los fármacos , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Pruebas de Toxicidad , Toxicología/métodos , Alternativas a las Pruebas en Animales , Animales , Encéfalo/embriología , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Humanos , Neuronas/metabolismo , Neuronas/patología , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Medición de Riesgo

RESUMEN

Micromass culture systems have been developed as three-dimensional organotypic in vitro alternatives to test developmental toxicity. We have optimized a murine-based embryonic midbrain micromass system in two genetic strains to evaluate neurodevelopmental effects of gold-cored silver nanoparticles (AgNPs) of differing sizes and coatings-20 nm AgCitrate, 110 nm AgCitrate, and 110 nm AgPVP. AgNPs are increasingly used in consumer, commercial, and medical products for their antimicrobial properties and observations of Ag in adult and fetal brain following in vivo exposures to AgNPs have led to concerns about the potential for AgNPs to elicit adverse effects on neurodevelopment and neurological function. Cytotoxicity was assessed at three time points of development by both nominal dose and by dosimetric dose. Ag dosimetry was assessed in cultures and the gold core component of the AgNPs was used as a tracer for determination of uptake of intact AgNPs and silver dissolution from particles in the culture system. Results by both nominal and dosimetric dose show cell death increased significantly in a dose-dependent manner at later time points (days 15 and 22 in vitro) that coincide with differentiation stages of development in both strains. When assessed by dosimetric dose, cultures were more sensitive to smaller particles, despite less uptake of Ag in smaller particles in both strains.

Asunto(s)

Citratos/toxicidad , Mesencéfalo/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Síndromes de Neurotoxicidad/etiología , Povidona/toxicidad , Plata/toxicidad , Pruebas de Toxicidad , Animales , Muerte Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacción Gen-Ambiente , Edad Gestacional , Mesencéfalo/embriología , Ratones Endogámicos C57BL , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/genética , Tamaño de la Partícula , Povidona/análogos & derivados , Medición de Riesgo , Especificidad de la Especie , Factores de Tiempo , Técnicas de Cultivo de Tejidos

RESUMEN

Superfund sites often consist of complex mixtures of polycyclic aromatic hydrocarbons (PAHs). It is widely recognized that PAHs pose risks to human and environmental health, but the risks posed by exposure to PAH mixtures are unclear. We constructed an environmentally relevant PAH mixture with the top 10 most prevalent PAHs (SM10) from a Superfund site derived from environmental passive sampling data. Using the zebrafish model, we measured body burden at 48 hours post fertilization (hpf) and evaluated the developmental and neurotoxicity of SM10 and the 10 individual constituents at 24 hours post fertilization (hpf) and 5 days post fertilization (dpf). Zebrafish embryos were exposed from 6 to 120 hpf to (1) the SM10 mixture, (2) a variety of individual PAHs: pyrene, fluoranthene, retene, benzo[a]anthracene, chrysene, naphthalene, acenaphthene, phenanthrene, fluorene, and 2-methylnaphthalene. We demonstrated that SM10 and only 3 of the individual PAHs were developmentally toxic. Subsequently, we constructed and exposed developing zebrafish to two sub-mixtures: SM3 (comprised of 3 of the developmentally toxicity PAHs) and SM7 (7 non-developmentally toxic PAHs). We found that the SM3 toxicity profile was similar to SM10, and SM7 unexpectedly elicited developmental toxicity unlike that seen with its individual components. The results demonstrated that the overall developmental toxicity in the mixtures could be explained using the general concentration addition model. To determine if exposures activated the AHR pathway, spatial expression of CYP1A was evaluated in the 10 individual PAHs and the 3 mixtures at 5 dpf. Results showed activation of AHR in the liver and vasculature for the mixtures and some individual PAHs. Embryos exposed to SM10 during development and raised in chemical-free water into adulthood exhibited decreased learning and responses to startle stimulus indicating that developmental SM10 exposures affect neurobehavior. Collectively, these results exemplify the utility of zebrafish to investigate the developmental and neurotoxicity of complex mixtures.

Asunto(s)

Contaminantes Ambientales/toxicidad , Sistema Nervioso/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Hidrocarburos Policíclicos Aromáticos/toxicidad , Pez Cebra/embriología , Animales , Hidrocarburo de Aril Hidroxilasas/biosíntesis , Conducta Animal/efectos de los fármacos , Carga Corporal (Radioterapia) , Relación Dosis-Respuesta a Droga , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Inducción Enzimática , Aprendizaje/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/embriología , Hígado/enzimología , Sistema Nervioso/embriología , Sistema Nervioso/fisiopatología , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/fisiopatología , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Medición de Riesgo , Pez Cebra/metabolismo

RESUMEN

Central nervous system side effects are one of the most frequently reported adverse reactions of fluoroquinolones (FQs). However, the mechanism is not fully understood. In this study, zebrafish ( Danio rerio) were used as a model system. We quantified neurobehavior by recording indicators with automated video-tracking and used liquid chromatography-tandem mass spectrometry to detect drug absorption in vivo. We studied embryotoxicity and effects on zebrafish locomotor activity of 17 typical FQs. In addition, we calculated the stable conformation of typical FQs in aqueous conditions. The relationships between structure, neurotoxicity, and embryotoxicity were analyzed. The results indicate: (1) The effects of FQs on zebrafish neurobehavior can be divided into four categories. Type I has no significant influence on locomotor activity. Type II suppresses locomotor activity. Type III inhibits at low concentration and stimulates at high concentration. Type IV stimulates and then suppresses (biphasic response). (2) Structural modifications of FQs can change toxicity properties in zebrafish. Cleavage of the C-7 piperazinyl structure decreases neurotoxicity but enhances embryotoxicity. The C-3 decarboxyl formation and 5-NH2 derivatives might enhance embryotoxicity and neurotoxicity. (3) There are two toxic functional groups. The piperazinyl structure at position C-7 (toxic functional group I) can cause primary reactions which may be by the inhibition of γ-aminobutyric acid receptors, and the nucleus containing a carboxyl group at position 3 (toxic functional group II) might cause a reaction secondary to the effect of toxic functional group I and reverse its effects.

Asunto(s)

Conducta Animal/efectos de los fármacos , Fluoroquinolonas/química , Fluoroquinolonas/toxicidad , Locomoción/efectos de los fármacos , Síndromes de Neurotoxicidad/patología , Animales , Cromatografía Liquida , Fluoroquinolonas/análisis , Estructura Molecular , Síndromes de Neurotoxicidad/embriología , Espectrometría de Masas en Tándem , Pez Cebra

RESUMEN

Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing. Since at the regulatory level, systematic testing of DNT is not a standard requirement within the EU or USA chemical legislation safety assessment, DNT testing is only performed in higher tiered testing triggered based on chemical structure activity relationships or evidence of neurotoxicity in systemic acute or repeated dose toxicity studies. However, these triggers are rarely used and, in addition, do not always serve as reliable indicators of DNT, as they are generally based on observations in adult rodents. Therefore, there is a pressing need for developing alternative methodologies that can reliably support identification of DNT triggers, and more rapidly and cost-effectively support the identification and characterization of chemicals with DNT potential. We propose to incorporate mechanistic knowledge and data derived from in vitro studies to support various regulatory applications including: (a) the identification of potential DNT triggers, (b) initial chemical screening and prioritization, (c) hazard identification and characterization, (d) chemical biological grouping, and (e) assessment of exposure to chemical mixtures. Ideally, currently available cellular neuronal/glial models derived from human induced pluripotent stem cells (hiPSCs) should be used as they allow evaluation of chemical impacts on key neurodevelopmental processes, by reproducing different windows of exposure during human brain development. A battery of DNT in vitro test methods derived from hiPSCs could generate valuable mechanistic data, speeding up the evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential.

Asunto(s)

Sistema Nervioso/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Pruebas de Toxicidad , Toxicología/métodos , Alternativas a las Pruebas en Animales , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Sistema Nervioso/embriología , Sistema Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/metabolismo , Formulación de Políticas , Relación Estructura-Actividad Cuantitativa , Medición de Riesgo , Toxicología/legislación & jurisprudencia

RESUMEN

Ethanol exposure during development causes fetal alcohol spectrum disorders (FASD). A large body of evidence shows that ethanol produces multiple abnormalities in the developing central nervous system (CNS), such as smaller brain size, reduced volume of cerebral white matter, permanent loss of neurons, and alterations in synaptogenesis and myelinogenesis. The effects of ethanol on the developing spinal cord, however, receive little attention and remain unclear. We used a third trimester equivalent mouse model to investigate the effect of ethanol on the developing spinal cord. Ethanol caused apoptosis and neurodegeneration in the dorsal horn neurons of mice of early postnatal days, which was accompanied by glial activation, macrophage infiltration, and increased expression of CCR2, a receptor for monocyte chemoattractant protein 1 (MCP-1). Ethanol-induced neuronal death during development resulted in permanent loss of spinal cord neurons in adult mice. Ethanol stimulated endoplasmic reticulum (ER) stress and oxidative stress, and activated glycogen synthase kinase 3ß (GSK3ß) and c-Jun N-terminal kinase (JNK) pathways. Knocking out MCP-1 or CCR2 made mice resistant to ethanol-induced apoptosis, ER stress, glial activation, and activation of GSK3ß and JNK. CCR2 knock out offered much better protection against ethanol-induced damage to the spinal cord. Thus, developmental ethanol exposure caused permanent loss of spinal cord neurons and CCR2 signaling played an important role in ethanol neurotoxicity.

Asunto(s)

Etanol/toxicidad , Trastornos del Espectro Alcohólico Fetal/metabolismo , Enfermedades Neurodegenerativas/embriología , Síndromes de Neurotoxicidad/embriología , Receptores CCR2/metabolismo , Transducción de Señal/efectos de los fármacos , Médula Espinal/embriología , Animales , Trastornos del Espectro Alcohólico Fetal/genética , Trastornos del Espectro Alcohólico Fetal/patología , Ratones , Ratones Noqueados , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/patología , Receptores CCR2/genética , Transducción de Señal/genética , Médula Espinal/patología

RESUMEN

Methamidophos is a representative organophosphate insecticide. The knowledge of its developmental neurotoxicity is limited, especially for zebrafish in the early stages of their life. Four hour post-fertilization (hpf) zebrafish embryos were exposed to several environmentally relevant concentrations of methamidophos (0, 25, and 500 µg/L) for up to 72 hpf. Locomotor behavior was then studied in the zebrafish larvae at this timepoint. Acridine orange (AO) staining was carried out in the zebrafish larvae, and the mRNA levels of genes associated with neural development (mbp and syn2a) were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The number of escape responders for mechanical stimulation was significantly decreased in exposed groups. AO staining showed noticeable signs of apoptosis mainly in the brain. In addition, the mRNA levels of mbp and syn2a were both significantly down-regulated in exposed groups. Our study provides the first evidence that methamidophos exposure can cause developmental neurotoxicity in the early stages of zebrafish life, which may be caused by the effect of methamidophos on neurodevelopmental genes and the activation of cell apoptosis in the brain.

Asunto(s)

Insecticidas/farmacología , Larva/efectos de los fármacos , Síndromes de Neurotoxicidad/embriología , Compuestos Organofosforados/farmacología , Compuestos Organotiofosforados/farmacología , Pez Cebra/embriología , Animales , Apoptosis/efectos de los fármacos , Embrión no Mamífero , Regulación del Desarrollo de la Expresión Génica , ARN Mensajero/genética

RESUMEN

In the present work, we investigated developmental toxicity of Paraquat (PQ), from the 1st or 6th day of mating and throughout the gestation period. We have examined several parameters, including toxicity indices, reproductive performance, sensorimotor development, as well as anxiety and cognitive performance of the offspring. Our results showed that exposure to 20mg/kg of Paraquat during the first days of pregnancy completely prevents pregnancy in treated mice, but from the 6th day of pregnancy, an alteration in fertility and reproductive parameters was observed. In offspring, the PQ was responsible for an overall delay of innate reflexes and a deficit in motor development. All exposed animals showed a decrease in the level of locomotor activity, increased levels of anxiety-like behavior and pronounced cognitive impairment in adulthood. These results demonstrated that Paraquat led to the onset of many behavioral changes that stem from the impairment of neuronal developmental processes in prenatally exposed mice.

Asunto(s)

Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Herbicidas/toxicidad , Síndromes de Neurotoxicidad/etiología , Paraquat/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Reacción de Prevención/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/embriología , Encéfalo/patología , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Reflejo de Enderezamiento/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante

RESUMEN

Many chemicals currently used are known to elicit nervous system effects. In addition, approximately 2000 new chemicals introduced annually have not yet undergone neurotoxicity testing. This review concentrated on motor development effects associated with exposure to environmental neurotoxicants to help identify critical windows of exposure and begin to assess data needs based on a subset of chemicals thoroughly reviewed by the Agency for Toxic Substances and Disease Registry (ATSDR) in Toxicological Profiles and Addenda. Multiple windows of sensitivity were identified that differed based on the maturity level of the neurological system at the time of exposure, as well as dose and exposure duration. Similar but distinct windows were found for both motor activity (GD 8-17 [rats], GD 12-14 and PND 3-10 [mice]) and motor function performance (insufficient data for rats, GD 12-17 [mice]). Identifying specific windows of sensitivity in animal studies was hampered by study designs oriented towards detection of neurotoxicity that occurred at any time throughout the developmental process. In conclusion, while this investigation identified some critical exposure windows for motor development effects, it demonstrates a need for more acute duration exposure studies based on neurodevelopmental windows, particularly during the exposure periods identified in this review.

Asunto(s)

Conducta Animal/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Actividad Motora/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Efectos Tardíos de la Exposición Prenatal , Pruebas de Toxicidad/métodos , Factores de Edad , Animales , Animales Recién Nacidos , Sistema Nervioso Central/embriología , Sistema Nervioso Central/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Edad Gestacional , Humanos , Ratones , Modelos Animales , Morfogénesis/efectos de los fármacos , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/fisiopatología , Embarazo , Ratas , Medición de Riesgo , Especificidad de la Especie , Factores de Tiempo

RESUMEN

The developing brain is highly vulnerable to the adverse effects of chemicals, resulting in neurodevelopmental disorders in humans. Currently, animal experiments in the rat are the gold standard for developmental neurotoxicity (DNT) testing; however, these guideline studies are insufficient in terms of animal use, time and costs and bear the issue of species extrapolation. Therefore, the necessity for alternative methods that predict DNT of chemicals faster, cheaper and with a high predictivity for humans is internationally agreed on. In this respect, we developed an in vitro model for DNT key event screening, which is based on primary human and rat neural progenitor cells grown as neurospheres. They are able to mimic basic processes of early fetal brain development and enable an investigation of species differences between humans and rodents in corresponding cellular models. The goal of this study was to investigate to what extent human and rat neurospheres were able to correctly predict the DNT potential of a well-characterized training set of nine chemicals by investigating effects on progenitor cell proliferation, migration and neuronal differentiation in parallel to cell viability, and to compare these chemical responses between human and rat neurospheres. We demonstrate that (1) by correlating these human and rat in vitro results to existing in vivo data, human and rat neurospheres classified most compounds correctly and thus may serve as a valuable component of a modular DNT testing strategy and (2) human and rat neurospheres differed in their sensitivity to most chemicals, reflecting toxicodynamic species differences of chemicals.

Asunto(s)

Proliferación Celular/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Síndromes de Neurotoxicidad/embriología , Animales , Técnicas de Cultivo de Célula , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Células-Madre Neurales/patología , Ratas , Especificidad de la Especie , Esferoides Celulares

RESUMEN

Trace elements have contributed unique insights into developmental neurotoxicity and serve as paradigms for such adverse effects. Many trace elements are retained in the body for long periods and can be easily measured to assess exposure by inexpensive analytical methods that became available several decades ago so that past and cumulated exposures could be easily characterized through analysis of biological samples, e.g. blood and urine. The first compelling evidence resulted from unfortunate poisoning events that allowed scrutiny of long-term outcomes of acute exposures that occurred during early development. Pursuant to this documentation, prospective studies of children's cohorts that applied sensitive neurobehavioral methods supported the notion that the brain is uniquely vulnerable to toxic damage during early development. Lead, methylmercury, and arsenic thereby serve as paradigm neurotoxicants that provide a reference for other substances that may have similar adverse effects. Less evidence is available on manganese, fluoride, and cadmium, but experience from the former trace elements suggest that, with time, adverse effects are likely to be documented at exposures previously thought to be low and safe.

Asunto(s)

Arsénico/toxicidad , Contaminantes Ambientales/toxicidad , Plomo/toxicidad , Compuestos de Metilmercurio/toxicidad , Modelos Biológicos , Neurogénesis/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Niño , Desarrollo Infantil/efectos de los fármacos , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Desarrollo Fetal/efectos de los fármacos , Humanos , Lactante , Masculino , Exposición Materna/efectos adversos , Síndromes de Neurotoxicidad/embriología , Síndromes de Neurotoxicidad/patología , Embarazo