RESUMEN
Lead (Pb) and stress co-occur as risk factors, share biological substrates and produce common adverse effects. We previously found that prenatal restraint stress (PS) or offspring stress (OS) could enhance maternal Pb-induced behavioral, brain neurotransmitter level and HPA axis changes. The current study examined how lifetime Pb exposure, consistent with human environmental exposure, interacts with stress. Dams were exposed to Pb beginning 2 mos prior to breeding (0, 50 or 150ppm in drinking water), PS on gestational days 16 and 17, or the combination. Offspring continued on the same Pb exposure as the dam. A subset of Pb+PS offspring also received 3 additional stress challenges (OS), yielding 9 exposure groups/gender: 0-NS, 0-PS, 0-OS, 50-NS, 50-PS, 50-OS, 150-NS, 150-PS and 150-OS. As with maternal Pb (Virgolini et al., 2008a), lifetime Pb and stress influenced Fixed Interval (FI) behavior primarily in females. Relative to 0-NS control, reductions in postreinforcement pause (PRP) times were seen only with combined Pb+PS (50-PS, 50-OS, 150-PS). Stress increased FI response rates when Pb alone was without effect (150-PS, 150-OS), but gradually mitigated rate increases produced by Pb alone (50-PS, 50-OS), effects that appear to be due primarily to PS, as they were of comparable magnitude in PS and OS groups. Individual subject data suggest that enhanced Pb and PS effects reflect increasing numbers of subjects shifting to the high end of the normal range of FI performance values, consistent with a dose-response type of Pb+stress additivity. Consistent with reports of cortico-striatal mediation of both interval timing (PRP) and FI rates, principal component analyses suggested potential mediation via altered frontal cortex norepinephrine, reduced nucleus accumbens dopaminergic control and enhanced striatal monoamine control. Altered FI performance, whether occurring through changes in response rate, PRP, or both, represent behavioral inefficiency and potentially sub-optimal or even dysfunctional resource/energy use.
Asunto(s)
Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Compuestos Organometálicos/toxicidad , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Animales Recién Nacidos , Conducta Animal/fisiología , Química Encefálica/fisiología , Femenino , Sistema Hipotálamo-Hipofisario/química , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/química , Sistema Hipófiso-Suprarrenal/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Distribución Aleatoria , Ratas , Ratas Long-Evans , Esquema de RefuerzoRESUMEN
This study sought to further understand how environmental conditions influence the outcomes of early developmental insults. It compared changes in monoamine levels in frontal cortex, nucleus accumbens and striatum of male and female Long-Evans rat offspring subjected to maternal Pb exposure (0, 50 or 150ppm in drinking water from 2 months pre-breeding until pup weaning)+/-prenatal (PS) (restraint on GD16-17) or PS+offspring stress (OS; three variable stress challenges to young adults) determined at 2 months of age and at 6 months of age in littermates subsequently exposed either to experimental manipulations (EM: daily handling and performance on an operant fixed interval (FI) schedule of food reward), or to no experience (NEM; time alone). Time alone (NEM conditions), even in normal (control) animals, modified the trajectory of neurochemical changes between 2 and 6 months across brain regions and monoamines. EM significantly modified the NEM trajectories, and except NE and striatal DA, which increased, blunted the changes in monoamine levels that occurred over time alone. Pb+/-stress modified the trajectory of monoamine changes in both EM and NEM conditions, but these predominated under NEM conditions. Stress-associated modifications, occurring mainly with NEM OS groups, were fully reversed by EM procedures, while reversals of Pb+/-stress-associated modifications occurred primarily in nucleus accumbens, a region critical to mediation of FI response rates. These results extend the known environmental conditions that modify developmental Pb+/-stress insults, which is critical to ultimately understanding whether early insults lead to adaptive or maladaptive behavior and to devising behavioral therapeutic strategies. That time alone and a set of EM conditions typically used as outcome measures in intervention studies can themselves invoke neurochemical changes, moreover, has significant implications for experimental design of such studies.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Encéfalo/crecimiento & desarrollo , Fármacos del Sistema Nervioso Central/toxicidad , Plomo/toxicidad , Efectos Tardíos de la Exposición Prenatal/metabolismo , Estrés Psicológico/metabolismo , Envejecimiento , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fármacos del Sistema Nervioso Central/administración & dosificación , Fármacos del Sistema Nervioso Central/sangre , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Femenino , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/crecimiento & desarrollo , Lóbulo Frontal/metabolismo , Plomo/administración & dosificación , Plomo/sangre , Masculino , Norepinefrina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/crecimiento & desarrollo , Núcleo Accumbens/metabolismo , Embarazo , Distribución Aleatoria , Ratas , Ratas Long-Evans , Factores de TiempoRESUMEN
Combined exposures to maternal lead (Pb) and prenatal stress (PS) can act synergistically to enhance behavioral and neurochemical toxicity in offspring. Maternal Pb itself causes permanent dysfunction of the body's major stress system, the hypothalamic pituitary adrenal (HPA) axis. The current study sought to determine the potential involvement of altered negative glucocorticoid feedback as a mechanistic basis of the effects in rats of maternal Pb (0, 50 or 150 ppm in drinking water beginning 2 mo prior to breeding), prenatal stress (PS; restraint on gestational days 16-17) and combined maternal Pb+PS in 8 mo old male and female offspring. Corticosterone changes were measured over 24 h following an i.p. injection stress containing vehicle or 100 or 300 microg/kg (females) or 100 or 150 microg/kg (males) dexamethasone (DEX). Both Pb and PS prolonged the time course of corticosterone reduction following vehicle injection stress. Pb effects were non-monotonic, with a greater impact at 50 vs. 150 ppm, particularly in males, where further enhancement occurred with PS. In accord with these findings, the efficacy of DEX in suppressing corticosterone was reduced by Pb and Pb+PS in both genders, with Pb efficacy enhanced by PS in females, over the first 6 h post-administration. A marked prolongation of DEX effects was found in males. Thus, Pb, PS and Pb+PS, sometimes additively, produced hypercortisolism in both genders, followed by hypocortisolism in males, consistent with HPA axis dysfunction. These findings may provide a plausible unifying biological mechanism for the reported links between Pb exposure and stress-associated diseases and disorders mediated via the HPA axis, including obesity, hypertension, diabetes, anxiety, schizophrenia and depression. They also suggest broadening of Pb screening programs to pregnant women in high stress environments.
Asunto(s)
Corticosterona/sangre , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Plomo/toxicidad , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Estrés Fisiológico , Animales , Animales Recién Nacidos , Dexametasona/administración & dosificación , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Sistema Hipotálamo-Hipofisario/metabolismo , Plomo/administración & dosificación , Masculino , Exposición Materna , Intercambio Materno-Fetal , Sistema Hipófiso-Suprarrenal/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Long-Evans , Factores Sexuales , Factores de TiempoRESUMEN
We previously demonstrated potentiated effects of maternal Pb exposure producing blood Pb(PbB) levels averaging 39microg/dl combined with prenatal restraint stress (PS) on stress challenge responsivity of female offspring as adults. The present study sought to determine if: (1) such interactions occurred at lower PbBs, (2) exhibited gender specificity, and (3) corticosterone and neurochemical changes contributed to behavioral outcomes. Rat dams were exposed to 0, 50 or 150ppm Pb acetate drinking water solutions from 2 mos prior to breeding through lactation (pup exposure ended at weaning; mean PbBs of dams at weaning were <1, 11 and 31microg/dl, respectively); a subset in each Pb group underwent prenatal restraint stress (PS) on gestational days 16-17. The effects of variable intermittent stress challenge (restraint, cold, novelty) on Fixed Interval (FI) schedule controlled behavior and corticosterone were examined in offspring when they were adults. Corticosterone changes were also measured in non-behaviorally tested (NFI) littermates. PS alone was associated with FI rate suppression in females and FI rate enhancement in males; Pb exposure blunted these effects in both genders, particularly following restraint stress. PS alone produced modest corticosterone elevation following restraint stress in adult females, but robust enhancements in males following all challenges. Pb exposure blunted these corticosterone changes in females, but further enhanced levels in males. Pb-associated changes showed linear concentration dependence in females, but non-linearity in males, with stronger or selective changes at 50ppm. Statistically, FI performance was associated with corticosterone changes in females, but with frontal cortical dopaminergic and serotonergic changes in males. Corticosterone changes differed markedly in FI vs. NFI groups in both genders, demonstrating a critical role for behavioral history and raising caution about extrapolating biochemical markers across such conditions. These findings demonstrate that maternal Pb interacts with prenatal stress to further modify both behavioral and corticosterone responses to stress challenge, thereby suggesting that studies of Pb in isolation from other disease risk factors will not reveal the extent of its adverse effects. These findings also underscore the critical need to extend screening programs for elevated Pb exposure, now restricted to young children, to pregnant, at risk, women.
Asunto(s)
Plomo/toxicidad , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Estrés Psicológico/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Corticosterona/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Plomo/sangre , Masculino , Embarazo , Distribución Aleatoria , Ratas , Ratas Long-Evans , Análisis de Regresión , Esquema de Refuerzo , Factores Sexuales , Factores de TiempoRESUMEN
Lead (Pb) exposure and elevated stress are co-occurring risk factors. Both impact brain mesolimbic dopamine/glutamate systems involved in cognitive functions. We previously found that maternal stress can potentiate Pb-related adverse effects in offspring at blood Pb levels averaging approximately 40 microg/dl. The current study of combined Pb exposure and stress sought to extend those results to lower levels of Pb exposure, and to examine relationships among consequences in offspring for fixed interval (FI) schedule-controlled behavior, neurochemistry and corticosterone levels. Dams were exposed to maternal Pb beginning 2 months prior to breeding (0, 50 or 150 ppm in drinking water), maternal restraint stress on gestational days 16 and 17 (MS), or the combination. In addition, a subset of offspring from each resultant treatment group was also exposed intermittently to variable stressors as adults (MS+OS). Marked "Pb-stress"-related increases in response rates on a fixed interval schedule, a behavioral performance with demonstrated sensitivity to Pb, occurred preferentially in female offspring even at mean blood Pb levels of 11 microg/dl when 50 ppm Pb was combined with maternal and offspring stress. Greater sensitivity of females to frontal cortex catecholamine changes may contribute to the elevated FI response rates as mesocorticolimbic systems are critical to the mediation of this behavior. Basal and final corticosterone levels of offspring used to evaluate FI performance differed significantly from those of non-behaviorally tested (NFI) littermates, demonstrating that purported mechanisms of Pb, stress or Pb/stress effects determined in non-behaviorally trained animals cannot necessarily be generalized to animals with behavioral histories. Finally, the persistent and permanent consequences of Pb, stress and Pb+stress in offspring of both genders suggest that Pb screening programs should include pregnant women at risk for elevated Pb exposure, and that stress should be considered as an additional risk factor. Pb+stress effects observed in the absence of either risk factor alone (i.e., potentiated effects) raise questions about the capacity of current hazard identification approaches to adequately identify human health risks posed by neurotoxicants.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Plomo/toxicidad , Exposición Materna , Efectos Tardíos de la Exposición Prenatal , Estrés Psicológico/fisiopatología , Análisis de Varianza , Animales , Catecolaminas/metabolismo , Condicionamiento Operante/efectos de los fármacos , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Femenino , Plomo/sangre , Masculino , Intercambio Materno-Fetal , Embarazo , Análisis de Componente Principal , Distribución Aleatoria , Ratas , Ratas Long-Evans , Factores SexualesRESUMEN
Lead (Pb) is a xenobiotic metal with no known essential function in cellular growth, proliferation, or signaling. Decades of research characterizing the toxicology of Pb have shown it to be a potent neurotoxicant, especially during nervous system development. New concepts in the neurotoxicology of Pb include advances in understanding the mechanisms and cellular specificity of Pb. Experimental studies have shown that stress can significantly alter the effects of Pb, effects that could potentially be mediated through alterations in the interactions of glucocorticoids with the mesocorticolimbic dopamine system of the brain. Elevated stress, with corresponding elevated glucocorticoid levels, has been postulated to contribute to the increased levels of many diseases and dysfunctions in low socioeconomic status populations. Cellular models of learning and memory have been utilized to investigate the potential mechanisms of Pb-induced cognitive deficits. Examination of long-term potentiation in the rodent hippocampus has revealed Pb-induced increases in threshold, decreases in magnitude, and shorter retention times of synaptic plasticity. Structural plasticity in the form of adult neurogenesis in the hippocampus is also impacted by Pb exposure. The action of Pb on glutamate release, NMDA receptor function, or structural plasticity may underlie perturbations in synaptic plasticity and contribute to learning impairments. In addition to providing insight into potential mechanisms of Pb-induced cognitive deficits, cellular models offer an opportunity to investigate direct effects of Pb on isolated biological substrates. A target of interest is the 78-kDa molecular chaperone glucose-regulated protein (GRP78). GRP78 chaperones the secretion of the cytokine interleukin-6 (IL-6) by astrocytes. In vitro evidence shows that Pb strongly binds to GRP78, induces GRP78 aggregation, and blocks IL-6 secretion in astroglial cells. These findings provide evidence for a significant chaperone deficiency in Pb-exposed astrocytes in culture. In the long term, chaperone deficiency could underlie protein conformational diseases such as Alzheimer's Disease (AD). Lead exposure in early life has been implicated in subsequent progression of amyloidogenesis in rodents during old age. This exposure resulted in an increase in proteins associated with AD pathology viz., beta-amyloid precursor protein (beta-APP), and beta-amyloid (Abeta). These four new lines of research comprise compelling evidence that exposures to Pb have adverse effects on the nervous system, that environmental factors increase nervous system susceptibility to Pb, and that exposures in early life may cause neurodegeneration in later life.
Asunto(s)
Intoxicación del Sistema Nervioso por Plomo/fisiopatología , Plomo/toxicidad , Estrés Fisiológico/complicaciones , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/fisiopatología , Animales , Chaperón BiP del Retículo Endoplásmico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Factores de TiempoRESUMEN
OBJECTIVES: Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a primary effect of interleukin-1 (IL-1), with elevated glucocorticoids considered a mechanism for negative feedback immunoregulation. However, there is little direct evidence of such a functional relationship between IL-1-mediated immunoregulation and neuroendocrine influences elicited by IL-1. Therefore, the goal of this study was to examine whether the known adjuvant effects of IL-1 are altered in the absence of neuroendocrine feedback due to adrenalectomy. METHODS: Male BALB/c mice subjected to adrenalectomy (ADX) or sham surgery were administered with saline or recombinant human IL-1beta (rhIL-1beta) and at the same time immunized with 100 microg ovalbumin (OVA). In vivo and in vitro measures of antigen-specific IgG antibody production, IL-6 production and spleen cell proliferation were taken 6 and 12 days later. RESULTS: It was demonstrated that administration of rhIL-1beta at a dose that activates the HPA axis resulted in a significant augmentation of serum anti- OVA IgG antibody levels. Interestingly, this augmentation was potentiated in ADX animals. In addition, the in vitro spleen cell memory IgG antibody response to OVA was significantly augmented in rhIL-1beta-treated animals, and again, further potentiated in ADX animals. Interestingly, while hrIL-1beta treatment augmented antigen-stimulated IL-6 production - suggesting an effect of IL-1 on antigen-specific T helper 2 cell memory formation - potentiation was not evident in ADX animals. CONCLUSIONS: These results are consistent with the concept of HPA axis-mediated neuroendocrine feedback on excessive immune responsiveness due to IL-1. Such feedback may prevent disturbances to the self-limiting functions of the immune system, which are important to the prevention of autoimmune diseases, some of which involve elevated IL-1 production.
Asunto(s)
Adrenalectomía , Formación de Anticuerpos/efectos de los fármacos , Interleucina-1/farmacología , Neuroinmunomodulación/efectos de los fármacos , Animales , Anticuerpos/sangre , Formación de Anticuerpos/inmunología , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Sistema Hipotálamo-Hipofisario/inmunología , Inmunoglobulina G/inmunología , Interleucina-6/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Neuroinmunomodulación/inmunología , Ovalbúmina/inmunología , Ovalbúmina/farmacología , Sistema Hipófiso-Suprarrenal/inmunología , Proteínas Recombinantes/farmacología , Bazo/citología , Bazo/inmunologíaRESUMEN
Three experiments assessed the effect of the similarity and timing of interpolated information on retroactive interference in human infants. After 3-month-olds learned to move a mobile (the cue) in a distinctive context by kicking, they were exposed to novel stimuli and were tested 24 hr later for recognition of their training stimuli. In Experiment 1, the interpolated cue, context, or both were novel. Retroactive interference occurred unless the interpolated and training stimuli shared no components. In Experiments 2 and 3, the timing of exposure to the interpolated context or cue, respectively, varied. A novel context impaired recognition after exposure delays up to 2 hr, whereas a novel cue impaired recognition after exposure delays up to 40 min. The finding that the cue is less vulnerable to retroactive interference than the context suggests that it is processed more rapidly. These experiments reveal that retroactive interference in infants depends on both the similarity and timing of the interpolated information.