RESUMEN
The exact causes of Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurological disorder due to loss of upper and/or lower motoneurons, remain elusive. Gene-environment interactions are believed to be an important factor in the development of ALS. We previously showed that in vivo exposure of mice overexpressing the human superoxide dismutase 1 (hSOD1) gene mutation (hSOD1G93A; G93A), a mouse model for ALS, to environmental neurotoxicant methylmercury (MeHg) accelerated the onset of ALS-like phenotype. Here we examined the time-course of effects of MeHg on AMPA receptor (AMPAR)-mediated currents in hypoglossal motoneurons in brainstem slices prepared from G93A, hSOD1wild-type (hWT) and non-carrier WT mice following in vivo exposure to MeHg. Mice were exposed daily to 3 ppm (approximately 0.7 mg/kg/day) MeHg via drinking water beginning at postnatal day 28 (P28) and continued until P47, 64 or 84, then acute brainstem slices were prepared, and spontaneous excitatory postsynaptic currents (sEPSCs) or AMPA-evoked currents were examined using whole cell patch-clamp recording technique. Brainstem slices of untreated littermates were prepared at the same time points to serve as control. MeHg exposure had no significant effect on either sEPSCs or AMPA-evoked currents in slices from hWT or WT mice during any of those exposure time periods under our experimental conditions. MeHg also did not cause any significant effect on sEPSCs or AMPA-currents in G93A hypoglossal motoneurons at P47 and P64. However, at P84, MeHg significantly increased amplitudes of both sEPSCs and AMPA-evoked currents in hypoglossal motineurons from G93A mice (p < 0.05), but not the sEPSC frequency, suggesting a postsynaptic action on AMPARs. MeHg exposure did not cause any significant effect on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs). Therefore, MeHg exposure in vivo caused differential effects on AMPARs in hypoglossal motoneurons from mice with different genetic backgrounds. MeHg appears to preferentially stimulate the AMPAR-mediated currents in G93A hypoglossal motoneurons in an exposure time-dependent manner, which may contribute to the AMPAR-mediated motoneuron excitotoxicity, thereby facilitating development of ALS-like phenotype.
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Esclerosis Amiotrófica Lateral , Compuestos de Metilmercurio , Ratones , Humanos , Animales , Superóxido Dismutasa-1 , Esclerosis Amiotrófica Lateral/inducido químicamente , Esclerosis Amiotrófica Lateral/genética , Compuestos de Metilmercurio/toxicidad , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , Superóxido Dismutasa/metabolismo , Ratones Transgénicos , Neuronas Motoras/metabolismo , Tronco Encefálico/metabolismo , Mutación , Modelos Animales de Enfermedad , Médula Espinal/metabolismoRESUMEN
BACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to lower vaccine-induced antibody concentrations in children, while data from adults remains limited and equivocal. Characteristics of PFAS exposure and age at vaccination may modify such effects. OBJECTIVE: We used the mass administration of novel COVID-19 vaccines to test the hypothesis that prior exposure to environmentally-relevant concentrations of PFAS affect antibody response to vaccines in adolescents and adults. METHODS: Between April and June 2021, 226 participants aged 12-90 years with a history of exposure to PFAS in drinking water and who received an mRNA COVID-19 vaccine participated in our prospective cohort study. SARS-CoV-2 anti-spike and anti-nucleocapsid antibodies (IgG) were quantified before the first and second vaccine doses and again at two follow-ups in the following months (up to 103 days post dose 1). Serum PFAS concentrations (n = 39 individual PFAS) were measured once for each participant during baseline, before their first vaccination. The association between PFAS exposure and immune response to vaccination was investigated using linear regression and generalized estimating equation (GEE) models with adjustment for covariates that affect antibody response. PFAS mixture effects were assessed using weighted quantile sum and Bayesian kernel machine regression methods. RESULTS: The geometric mean (standard deviation) of perfluorooctane sulfonate and perfluorooctanoic acid serum concentrations in this population was 10.49 (3.22) and 3.90 (4.90) µg/L, respectively. PFAS concentrations were not associated with peak anti-spike antibody response, the initial increase in anti-spike antibody response following vaccination, or the waning over time of the anti-spike antibody response. Neither individual PFAS concentrations nor their evaluation as a mixture was associated with antibody response to mRNA vaccination against COVID-19. IMPACT STATEMENT: Given the importance of understanding vaccine response among populations exposed to environmental contaminants and the current gaps in understanding this relationship outside of early life/childhood vaccinations, our manuscript contributes meaningful data from an adolescent and adult population receiving a novel vaccination.
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COVID-19 , Agua Potable , Fluorocarburos , Vacunas , Adulto , Niño , Adolescente , Humanos , Vacunas contra la COVID-19 , Teorema de Bayes , Estudios Prospectivos , COVID-19/prevención & control , SARS-CoV-2 , Vacunación , InmunidadRESUMEN
PURPOSE OF REVIEW: Gene-environment (GxE) interactions likely contribute to numerous diseases, but are often difficult to model in the laboratory. Such interactions have been widely hypothesized for amyotrophic lateral sclerosis (ALS); recent controlled laboratory studies are discussed here and hypotheses related to possible mechanisms of action are offered. Using methylmercury exposure and mutated SOD1 to model the impacts of such an interaction, we interpret evidence about their respective mechanisms of toxicity to interrogate the possibility of additive (or synergistic) effects when combined. RECENT FINDINGS: Recent work has converged on mechanisms of calcium-mediated glutamate excitotoxicity as a likely contributor in one model of a gene-environment interaction affecting the onset and progression of ALS-like phenotype. The current experimental literature on mechanisms of metal-induced neuronal injury and their relevant interactions with genetic contributions in ALS is sparse, but we describe those studies here and offer several integrative hypotheses about the likely mechanisms involved.
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Esclerosis Amiotrófica Lateral/fisiopatología , Interacción Gen-Ambiente , Compuestos de Metilmercurio/toxicidad , Superóxido Dismutasa/toxicidad , Esclerosis Amiotrófica Lateral/inducido químicamente , Calcio , Depuradores de Radicales Libres , Ácido Glutámico , Humanos , Receptores AMPARESUMEN
Polybrominated diphenyl ethers (PBDEs) and their metabolites (e.g., hydroxylated BDEs [OH-BDEs]) are contaminants frequently detected together in human tissues and are structurally similar to thyroid hormones. Thyroid hormones partially mediate metamorphic transitions between life stages in zebrafish, making this a critical developmental window that may be vulnerable to chemicals disrupting thyroid signaling. In the present study, zebrafish were exposed to 6-OH-BDE-47 (30 nM; 15 µg/L) alone, or to a low-dose (30 µg/L) or high-dose (600 µg/L) mixture of PentaBDEs, 6-OH-BDE-47 (0.5-6 µg/L), and 2,4,6-tribromophenol (5-100 µg/L) during juvenile development (9-23 d postfertilization) and evaluated for developmental endpoints mediated by thyroid hormone signaling. Fish were sampled at 3 time points and examined for developmental and skeletal morphology, apical thyroid and skeletal gene markers, and modifications in swimming behavior (as adults). Exposure to the high-dose mixture resulted in >85% mortality within 1 wk of exposure, despite being below reported acute toxicity thresholds for individual congeners. The low-dose mixture and 6-OH-BDE-47 groups exhibited reductions in body length and delayed maturation, specifically relating to swim bladder, fin, and pigmentation development. Reduced skeletal ossification was also observed in 6-OH-BDE-47-treated fish. Assessment of thyroid and osteochondral gene regulatory networks demonstrated significantly increased expression of genes that regulate skeletal development and thyroid hormones. Overall, these results indicate that exposures to PBDE/OH-BDE mixtures adversely impact zebrafish maturation during metamorphosis. Environ Toxicol Chem 2017;36:36-48. © 2016 SETAC.
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Éteres Difenilos Halogenados/toxicidad , Osteogénesis/efectos de los fármacos , Bifenilos Polibrominados/toxicidad , Hormonas Tiroideas/metabolismo , Pez Cebra/crecimiento & desarrollo , Adulto , Animales , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Éteres Difenilos Halogenados/metabolismo , Humanos , Osteogénesis/genética , Bifenilos Polibrominados/metabolismo , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Hormonas Tiroideas/genética , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
BACKGROUND: Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities. METHODS: During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0 to 5dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2nM) or valproic acid (0, 0.5, 5.0 or 50µM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance). RESULTS: There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation. CONCLUSIONS: Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed.
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Conducta Animal/efectos de los fármacos , Tretinoina/efectos adversos , Ácido Valproico/efectos adversos , Pez Cebra/crecimiento & desarrollo , Animales , Reacción de Prevención/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Habituación Psicofisiológica/efectos de los fármacos , Larva/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Conducta SocialRESUMEN
Cigarette smoke has been associated with a number of pathologies; however, the mechanisms leading to developmental effects are yet to be fully understood. The zebrafish embryo is regarded as a 'bridge model'; however, not many studies examined its applicability to cigarette smoke toxicity. This study examined the effects of total particulate matter (TPM) from 3R4F reference cigarettes on the early development of zebrafish (Danio rerio). Zebrafish embryos were exposed to two concentrations of TPM (0.4 and 1.4 µg/mL equi-nicotine units) or nicotine at equivalent doses. The exposures began at 2h post-fertilization (hpf) and lasted until 96 hpf. Several physiological parameters were assessed during or after the exposure. We show that TPM increased mortality, delayed hatching, and increased the incidence of deformities in zebrafish. TPM exposure also increased the incidence of hemorrhage and disrupted the angiogenesis of the major vessels in the brain. Moreover, TPM exposure reduced the larval body length, decreased the heart rate, and reduced the metabolic rate. Biomarkers of xenobiotic metabolism and oxidative stress were also affected. TPM-exposed zebrafish also differed behaviorally: at 24 hpf the embryos had a higher frequency of spontaneous contractions and at 144 hpf the larvae displayed swimming hyperactivity. This study demonstrates that TPM disrupts several aspects of early development in zebrafish. The effects reported for TPM were not attributable to nicotine, since embryos treated with nicotine alone did not differ significantly from the control group. Collectively, our work illustrates the utility of zebrafish as an alternative model to evaluate the toxic effects of cigarette smoke constituents.
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Conducta Animal/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Nicotina/toxicidad , Agonistas Nicotínicos/toxicidad , Material Particulado/toxicidad , Análisis de Varianza , Animales , Citocromo P-450 CYP1A1/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Embrión no Mamífero/efectos de los fármacos , Hemoglobinas/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Teratógenos , Xenobióticos/metabolismo , Pez CebraRESUMEN
Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants that are widely detected in the environment, biota, and humans. In mammals, PBDEs can be oxidatively metabolized to form hydroxylated polybrominated diphenyl ethers (OH-BDEs). While studies have examined behavioral deficits or alterations induced by exposure to PBDEs in both rodents and fish, no study to date has explored behavioral effects from exposure to OH-BDEs, which have been shown to have greater endocrine disrupting potential compared to PBDEs. In the present study, zebrafish (Danio rerio) were exposed during embryonic and larval development (0-6 days post fertilization, dpf) to a PBDE metabolite, 6-hydroxy, 2,2',4,4' tetrabromodiphenyl ether (10-50 nM) and then examined for short and long-term behavioral effects. Exposed zebrafish tested as larvae (6 dpf) showed an altered swimming response to light-dark transitions, exhibiting hypoactivity in light periods compared to control fish. When fish exposed from 0-6 dpf were tested as juveniles (45 dpf), they showed an increased fear response and hyperactivity in response to tests of novel environment exploration and habituation learning. These results demonstrate that early life exposure to a PBDE metabolite can have immediate or later life (more than a month after exposure) effects on activity levels, habituation, and fear/anxiety.
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Retardadores de Llama/toxicidad , Éteres Difenilos Halogenados/toxicidad , Actividad Motora/efectos de los fármacos , Bifenilos Polibrominados/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Miedo/efectos de los fármacos , Fotoperiodo , Reflejo de Sobresalto/efectos de los fármacos , Natación , Pez Cebra/embriologíaRESUMEN
BACKGROUND: Neonicotinoid insecticides are becoming more widely applied as organophosphate (OP) insecticides are decreasing in use. Because of their relative specificity to insect nicotinic receptors, they are thought to have reduced risk of neurotoxicity in vertebrates. However, there is scant published literature concerning the neurobehavioral effects of developmental exposure of vertebrates to neonicotinoids. METHODS: Using zebrafish, we investigated the neurobehavioral effects of developmental exposure to imidacloprid, a prototypic neonicotinoid pesticide. Nicotine was also administered for comparison. Zebrafish were exposed via immersion in aqueous solutions containing 45 µM or 60 µM of imidacloprid or nicotine (or vehicle control) from 4h to 5d post fertilization. The functional effects of developmental exposure to both imidacloprid and nicotine were assessed in larvae using an activity assay and during adolescence and adulthood using a battery of neurobehavioral assays, including assessment of sensorimotor response and habituation in a tactile startle test, novel tank swimming, and shoaling behavior. RESULTS: In larvae, developmental imidacloprid exposure at both doses significantly decreased swimming activity. The 5D strains of zebrafish were more sensitive to both nicotine and imidacloprid than the AB* strain. In adolescent and adult fish, developmental exposure to imidacloprid significantly decreased novel tank exploration and increased sensorimotor response to startle stimuli. While nicotine did not affect novel tank swimming, it increased sensorimotor response to startle stimuli at the low dose. No effects of either compound were found on shoaling behavior or habituation to a startling stimulus. DISCUSSION: Early developmental exposure to imidacloprid has both early-life and persisting effects on neurobehavioral function in zebrafish. Its developmental neurotoxicity should be further investigated.
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Conducta Animal/efectos de los fármacos , Imidazoles/toxicidad , Insecticidas/toxicidad , Nitrocompuestos/toxicidad , Pez Cebra/crecimiento & desarrollo , Animales , Colinérgicos/toxicidad , Conducta Exploratoria/efectos de los fármacos , Habituación Psicofisiológica/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Neonicotinoides , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Conducta Social , NataciónRESUMEN
Over the last decade, zebrafish (Danio rerio) have become valuable as a complementary model in behavioral pharmacology, opening a new avenue for understanding the relationships between drug action and behavior. This species offers a useful intermediate approach bridging the gap between in vitro studies and traditional mammalian models. Zebrafish offer great advantages of economy compared to their rodent counterparts, their complex brains and behavioral repertoire offer great translational potential relative to in vitro models. The development and validation of a variety of tests to measure behavior, including cognition, in zebrafish have set the stage for the use of this animal for behavioral pharmacology studies. This has led to research into the basic mechanisms of cognitive function as well as screening for potential cognition-improving drug therapies, among other lines of research. As with all models, zebrafish have limitations, which span pharmacokinetic challenges to difficulties quantifying behavior. The use, efficacy and limitations associated with a zebrafish model of cognitive function are discussed in this review, within the context of behavioral pharmacology.
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Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Memoria/efectos de los fármacos , Memoria/fisiología , Pez Cebra/fisiología , Animales , Cognición/efectos de los fármacos , Cognición/fisiología , Función Ejecutiva/efectos de los fármacos , Función Ejecutiva/fisiología , Modelos Animales , Psicotrópicos/farmacologíaRESUMEN
Adult-onset methylmercury (MeHg) exposure is thought to result primarily in sensory and motor deficits but effects on learning are poorly understood. One mechanism by which chronic MeHg may exert its neurotoxicity is via sustained disruption of intracellular calcium homeostasis, with a consequent increase of intracellular Ca(2+) ions in vulnerable neurons. A biochemically heterogeneous group of compounds, calcium channel blockers, have been shown in vitro to attenuate MeHg's toxicity. To evaluate the role of calcium antagonism in MeHg toxicity in vivo, adult BALB/c mice were exposed chronically to 0 or 15 ppm of Hg (as MeHg) via drinking water and to nimodipine, a dihydropryidine, L-type Ca(2+) channel blocker with action in the CNS. Nimodipine was administered orally in diets (0, 20, or 200 ppm, producing approximately 0, 2, or 20 mg/kg/day of nimodipine). An incremental repeated acquisition (IRA) of response chains procedure was used to detect MeHg-induced deficits in learning or motoric function and to evaluate possible neuroprotection by nimodipine. MeHg impaired performance on the IRA task, and this was partially or completely blocked by dietary nimodipine, depending on dose. Measures of learning co-varied with measures of motoric function as indicated by overall response rate. Nimodipine delayed or prevented the behavioral toxicity of MeHg exposure as evidenced by IRA performance; effects on learning seemed secondary to response rate decreases.
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Encéfalo/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Dieta , Intoxicación del Sistema Nervioso por Mercurio/prevención & control , Compuestos de Metilmercurio , Nimodipina/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Aprendizaje/efectos de los fármacos , Masculino , Intoxicación del Sistema Nervioso por Mercurio/etiología , Intoxicación del Sistema Nervioso por Mercurio/metabolismo , Intoxicación del Sistema Nervioso por Mercurio/fisiopatología , Intoxicación del Sistema Nervioso por Mercurio/psicología , Ratones , Ratones Endogámicos BALB C , Actividad Motora/efectos de los fármacos , Factores de TiempoRESUMEN
A recently developed model posits that a bout of operant responding comprises three different components: bout initiation rate, within-bout response rate and bout length. Each parameter is thought to be affected by different classes of variables. Pentobarbital was used to assess the independence and sensitivity of these parameters in two mouse strains, BALB/c and C57BL/6, selected because of their different behavioral characteristics. With or without a running wheel present, BALB/c and C57BL/6 mice nose-poked under a Percentile 10:0.5 schedule designed to select high response rates while holding reinforcement rate constant. Baseline rates of nose-poking were higher for BALB/c mice than for C57BL/6 mice, but no strain difference occurred in baseline distance run. Nose-poking occurred at a higher rate when the wheel was absent from the chamber for both strains, and this was due to longer bout lengths and higher bout initiation rates. Nose-poke rates were increased by the 5.6-17 mg/kg doses of pentobarbital, especially in C57BL/6 mice. Pentobarbital only decreased running. No strain differences in pentobarbital sensitivity were observed for running. Whether reinforcement was extrinsic or intrinsic to the response was hypothesized to influence pentobarbital's effects. The different bout parameters helped dissect pentobarbital's effects and were selectively affected by pentobarbital.
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Pentobarbital/farmacología , Animales , Conducta Animal , Condicionamiento Operante , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Especificidad de la EspecieRESUMEN
BALB/c (n=8) and C57BL/6 (n=11) male mice were trained under an incremental repeated acquisition (IRA) procedure using two distinct training procedures: forward and backward chaining. A new metric for assessing progress on the IRA procedure, progress quotient (PQ), quantified progress as the product of chain length and number of reinforcers earned during a session divided by the total number of reinforcers earned. BALB/c mice progressed further, had higher overall responding, earned more reinforcers, and acquired the response sequences faster than the C57BL/6 mice on both training procedures. There were only minimal effects of training procedure for either strain. The strain differences found between BALB/c and C57BL/6 mice confirm the importance of genetic background to behavior. C57BL/6 mice may be deficient in learning as compared with BALB/c mice but other contributing factors probably include overall responding, motivation, and more rapid satiation or habituation to sucrose reinforcement by the C57BL/6 mice. PQ is a sensitive and valid measure of progress for use in studies of mastery-based incremental repeated acquisition and BALB/c mice perform this challenging learning task better than do C57BL/6 mice.
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Desempeño Psicomotor/fisiología , Aprendizaje Seriado/fisiología , Animales , Conducta Animal/fisiología , Condicionamiento Operante/fisiología , Interpretación Estadística de Datos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Esquema de Refuerzo , Especificidad de la EspecieRESUMEN
RATIONALE: Low doses of D: -amphetamine may enhance learning, depending on the conditions under which learning is studied. OBJECTIVE: The objective of this study is to evaluate the sensitivity of procedural variations of an incremental repeated acquisition procedure to very low-dose D: -amphetamine administration. METHODS: A 60-min session began with a one-link chain (single lever press) that incremented to a maximum of a four-link chain using three levers: left (L), right (R), and back (B). Backward (five rats) and forward (five rats) training procedures were used to build the chain. In pseudo-randomized presentations, a performance session (same chain every session) and a learning session (chain differed from session to session) were imposed. Some learning chains had an embedded repeated response (e.g., LRRB), and others had no such repeat (e.g., LRLB). The product of chain length and number of reinforcers divided by total reinforcers was the primary marker of progress during a session (i.e., progress quotient (PQ)). After behavior stabilized, D: -amphetamine (0.01-3.0 mg/kg, i.p.) was administered. RESULTS: Acquisition was superior for the backward training group during non-repeating learning sessions, across all but the highest doses of D: -amphetamine. Very low, clinically relevant, doses of D: -amphetamine improved acquisition for the backward training group during repeating learning sessions. CONCLUSIONS: Under some conditions, low doses of D: -amphetamine enhanced learning for one training procedure group. A novel dependent measure ("PQ") was a superior marker of progress on this mastery-based learning task.