Early exposure to Aroclor 1254 in vivo disrupts the functional synaptic development of newborn hippocampal granule cells

Neurogenesis in the dentate gyrus is sensitive to endogenous and exogenous factors that influence hippocampal function. Ongoing neurogenesis and the integration of these new neurons throughout life thus may provide a sensitive indicator of environmental stress. We examined the effects of Aroclor 1254 (A1254), a mixture of polychlorinated biphenyls (PCBs), on the development and function of newly generated dentate granule cells. Early exposure to A1254 has been associated with learning impairment in children, suggesting potential impact on the development of hippocampus and/or cortical circuits. Oral A1254 (from the 6th day of gestation to postnatal day 21) produced the expected increase in PCB levels in brain at postnatal day 21, which persisted at lower levels into adulthood. A1254 did not affect the proliferation or survival of newborn neurons in immature animals nor did it cause overt changes in neuronal morphology. However, A1254 occluded the normal developmental increase in sEPSC frequency in the third post‐mitotic week without altering the average sEPSC amplitude. Our results suggest that early exposure to PCBs can disrupt excitatory synaptic function during a period of active synaptogenesis, and thus could contribute to the cognitive effects noted in children exposed to PCBs.     

Perinatal exposure to polychlorinated biphenyls Aroclor 1016 or 1254 did not alter brain catecholamines nor delayed alternation performancein Long-Evans rats

Several reports have indicated that polychlorinated biphenyls (PCB) altered development of biogenic amine systems in the brain, impaired behavioral performances, and disrupted maturation of the thyroid axis. The current study examines whether these developmental effects of PCB are correlated. Timed-pregnant Long-Evans rats were gavaged with the PCB mixture Aroclor 1016 (A-1016, 10 mg/kg) from gestation day (GD) 6 to parturition. Some pups continued to receive daily oral administration of PCB (10 mg/kg) until weaning at postnatal day (PD) 21. Another group of pregnant rats was given Aroclor 1254 (A-1254, 8 mg/kg) daily from GD 6 to weaning. At various age intervals, rats were sacrificed and six brain regions (prefrontal cortex, striatum, hippocampus, diencephalon, cerebellum, midbrain + brain stem) were removed and analyzed for dopamine (DA) and norepinephrine (NE) levels by high-performance liquid chromatography. In addition, transmitter turnover rates were determined after an acute treatment of alpha-methyl-p-tyrosine. Serum samples were collected and analyzed for triiodothyronine (T(3)) and thyroxine (T(4)) by radioimmunoassay. Behaviorally, rats were evaluated for spatial learning and memory by means of T-maze delayed alternation and Morris maze tasks on PD 23 and PD 70, respectively. A-1016 treatment produced only small and transient reductions in body weight gain, and generally did not alter the thyroid status of the developing rats. It did not cause any significant changes in DA or NE level, or turnover rate in any of the brain regions examined, nor did it affect behavioral measures of cognitive development. In contrast, perinatal exposure to A-1254 led to marked deficits of growth, and sharply reduced serum T(4), although T(3) remained largely unaffected. Accompanying this hormonal imbalance, brain NE contents in the A-1254-exposed pups were reduced, although brain DA was not significantly affected; no demonstrable neurobehavioral deficits were seen in the T-maze or Morris maze tests. These results indicated that development of central noradrenergic neurons was compromised by perinatal exposure to A-1254 but not A-1016, and both PCB mixtures failed to alter behavioral performances.     

Sub-chronic exposure of the adult rat to Aroclor 1254 yields regionally-specific changes in central dopaminergic function

Laboratory rats were exposed to chow adulterated with either 500 or 1000 ppm Aroclor 1254 for 30 days. Analysis of biogenic amines and their metabolites in the dorsal frontal cortex, lateral olfactory tract, striatum, basal hypothalamus, hippocampus and brainstem revealed significant decreases in dopamine concentrations and metabolism in only the striatum and lateral olfactory tract. Concentrations of individual PCB congeners in the striatum, lateral olfactory tract and hippocampus were measured by gas chromatography with electron capture detection. Neither total concentration nor variations in concentrations of individual congeners between regions could explain this regional specificity. The susceptibility of the striatum and lateral olfactory tract to insult by PCBs may be due to their innervation by midbrain dopaminergic neurons which have been shown to be particularly sensitive to insult from environmental, infectious and pharmacologic agents.     

Permanently compromised NADPH-diaphorase activity within the osmotically activated supraoptic nucleus after in utero but not adult exposure to Aroclor 1254

Stimulated vasopressin (VP) release from magnocellular neuroendocrine cells in the supraoptic nucleus (SON) of hyperosmotic rats is inhibited by treatment with the industrial polychlorinated biphenyl (PCB) mixture, Aroclor 1254. Because VP responses to hyperosmotic stimulation are regulated by nitric oxide (NO) signaling, we studied NO synthase (NOS) activity in the SON of hyperosmotic rats as potential target of PCB-induced disruption of neuroendocrine processes necessary for osmoregulation. To examine PCB-induced changes in NOS activity under normosmotic and hyperosmotic conditions, male Sprague-Dawley rats were exposed to Aroclor 1254 (30 mg/kg/day) in utero and NADPH-diaphorase (NADPH-d) activity was assessed in SON sections at three ages: postnatal day 10, early adult (3–5 months) or late adult (14–16 months). Hyperosmotic treatment increased mean NADPH-d staining density of oil hyperosmotic controls by 19.9% in early adults and 58% in late adulthood vs normosmotic controls. In utero exposure to PCBs reduced hyperosmotic-induced upregulation of NADPH-d activity to control levels in early adults and by 28% in late adults. Basal NADPH-d was reduced in postnatal rats. Rats receiving PCB exposure as early adults orally for 14 days displayed normal responses. Our findings show that developmental but not adult exposure to PCBs significantly reduces NOS responses to hyperosmolality in neuroendocrine cells. Moreover, reduced NADPH-d activity produced by in utero exposure persisted in stimulated late adult rats concomitant with reduced osmoregulatory capacity vs oil controls (375 ± 9 vs 349 ± 5 mOsm/L). These findings suggest that developmental PCBs permanently compromise NOS signaling in the activated neuroendocrine hypothalamus with potential osmoregulatory consequences.     

Repeated exposure of adult rats to Aroclor 1254 induces neuronal injury and impairs the neurochemical manifestations of the NMDA receptor-mediated intracellular signaling in the hippocampus

Aroclor 1254 is a mixture of polychlorinated biphenyls (PCBs), a class of environmental toxins which cause a wide spectrum of neurotoxic effects. Learning and memory deficits are the profound effects of PCBs which may be related to hippocampal dysfunction. To get insight into the underlying neurochemical mechanisms, we employed the microdialysis technique to investigate the effect of repeated exposure of adult male Wistar rats to Aroclor 1254 (10 mg/kg b.w., daily, ig., for 14 days), on the neurochemical parameters of NMDA receptor-mediated glutamatergic signaling in the hippocampus in vivo assessed using the microdialysis technique. The results demonstrated that exposure to Aroclor 1254, which was associated with substantial neuronal damage and loss in the hippocampus, markedly decreased the NMDA-induced extracellular accumulation of newly loaded ⁴⁵CaCl₂, cGMP and glutamate, and reduced the basal content of the NO precursor, arginine, indicating inhibition of the NMDA/NO/cGMP pathway. Aroclor 1254 exposure also decreased the basal microdialysate content of glutamate and glutamine, which may cause inadequate supply of the neurotransmitter glutamate, while the level of two other neuroactive amino acids, aspartate or taurine was not affected by the exposure. The results underscore neuronal lesion and inhibition of NMDA receptor-mediated glutamatergic signaling in hippocampus as a potential major contributor to the cognitive deficits associated with exposure to PCB.     

Developmental exposure to a commercial PCB mixture (Aroclor 1254) produces a persistent impairment in long-term potentiation in the rat dentate gyrus in vivo

Developmental exposure to polycholorinated biphenyls (PCBs) has been associated with cognitive deficits in humans and laboratory animals. The present study sought to examine synaptic plasticity in the hippocampus, a brain region critical for some types of memory function, in animals exposed to PCBs early in development. Pregnant Long–Evans rats were administered either corn oil (control) or 6 mg/kg/day of a commercial PCB mixture, Aroclor 1254 (A1254) by gavage from gestational day (GD) 6 until pups were weaned on postnatal day (PND) 21. In adult male offspring (3–6 months of age), field potentials evoked by perforant path stimulation were recorded in the dentate gyrus under urethane anesthesia. Input/output (I/O) functions were assessed by averaging the response evoked in the dentate gyrus to stimulus pulses delivered to the perforant path in an ascending intensity series. Long-term potentiation (LTP) was induced by delivering a series of brief high frequency (400 Hz) train bursts to the perforant path at a moderate stimulus intensity and I/O functions were reassessed 1 h later. No differences in baseline synaptic population spike (PS) and minor effects on excitatory postsynaptic potential (EPSP) slope amplitudes were discerned between the groups prior to train delivery. Post-train I/O functions, however, revealed a 50% decrement in the magnitude of LTP in PCB-exposed animals. These data are the first to demonstrate persistent decrements in hippocampal synaptic plasticity in the intact animal following developmental exposure to PCBs. Disruption of early brain ontogeny due to developmental PCB exposure may underlie perturbations in the neurological substrates that support synaptic plasticity and contribute to deficits in LTP and learning that persist into adulthood.     

Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat

The persisting need for effective clinical treatment of chemotherapy-induced neurotoxicity (CIN) motivates critical evaluation of preclinical models of CIN for their translational relevance. The present study aimed to provide the first quantitative evaluation of neural tissue exposed in vivo to a platinum-based anticancer compound, oxaliplatin (OX) during and after two commonly used dosing regimens: slow IV infusion used clinically and bolus IP injection used preclinically. Inductively-coupled plasma mass spectrometry analysis of dorsal root ganglia indicated that while differences in the temporal dynamics of platinum distribution exist, key drivers of neurotoxicity, e.g. peak concentrations and exposure, were not different across the two routes of administration. We conclude that the IP route of OX administration achieves clinically relevant pharmacokinetic exposure of neural tissues in a rodent model of CIN.     

Intranasal administration: a prospective drug delivery route to the brain

In recent decades the interest in intranasal drug administration is increased, not only for the treatment of acute and chronic diseases of the nasal cavity but mainly for drug delivery to the brain. The advantages of intranasal drug delivery (IDD) are the high bioavailability of drugs, rapid development of therapeutic effects, non-invasiveness, painlessness, and simple and comfortable application. In order to reach a high extent and rate of drug absorption and bioavailability, various approaches have been suggested, including application of micro- and nanocarriers. Intranasal administration is used for a wide variety of drugs, including proteins, peptides, and highly polar compounds. The opportunity to use IDD to the brain opens new promise for the effective treatment of cerebral pathologies.     

Opioid addiction and pregnancy: perinatal exposure to buprenorphine affects myelination in the developing brain

Buprenorphine is a mu-opioid receptor partial agonist and kappa-opioid receptor antagonist currently on trials for the management of pregnant opioid-dependent addicts. However, little is known about the effects of buprenorphine on brain development. Oligodendrocytes express opioid receptors in a developmentally regulated manner and thus, it is logical to hypothesize that perinatal exposure to buprenorphine could affect myelination. To investigate this possibility, pregnant rats were implanted with minipumps to deliver buprenorphine at 0.3 or 1 mg/kg/day. Analysis of their pups at different postnatal ages indicated that exposure to 0.3 mg/kg/day buprenorphine caused an accelerated and significant increase in the brain expression of all myelin basic protein (MBP) splicing isoforms. In contrast, treatment with the higher dose caused a developmental delay in MBP expression. Examination of corpus callosum at 26-days of age indicated that both buprenorphine doses cause a significant increase in the caliber of the myelinated axons. Surprisingly, these axons have a disproportionately thinner myelin sheath, suggesting alterations at the level of axon-glial interactions. Analysis of myelin associated glycoprotein (MAG) expression and glycosylation indicated that this molecule may play a crucial role in mediating these effects. Co-immunoprecipitation studies also suggested a mechanism involving a MAG-dependent activation of the Src-family tyrosine kinase Fyn. These results support the idea that opioid signaling plays an important role in regulating myelination in vivo and stress the need for further studies investigating potential effects of perinatal buprenorphine exposure on brain development.     

Deliberate exposure to motor vehicle exhaust gas: the psychosocial profile of attempted suicide

OBJECTIVE: Deliberate exposure to motor vehicle exhaust gas has become the second most commonly used method of suicide in Australia. In an attempt to understand the factors contributing to the rise in popularity of this method, the psychosocial profiles, factors influencing method choice and circumstances of the act of self-harm were examined in a group of survivors. METHOD: A cross-sectional cohort study of 30 patients presenting for hyperbaric oxygen treatment having survived deliberate exposure to car exhaust gas was undertaken. A structured clinical interview was administered together with scales measuring depression, hopelessness and suicidal intent. Daily assessment of mental state and cognitive function was performed. RESULTS: Factors common to the majority of subjects included male gender, age group of 20-50 years, and alcohol abuse. Relationship discord was the most common precipitating factor. Reasons given for choice of this method included the availability and accessibility of motor vehicles, painlessness, awareness that the method was lethal, knowledge of another person's successful suicide by this method and awareness of the method through media portrayal. Most of the cars used did not have engines fitted with catalytic converters, substantially increasing the risk of toxicity. Regret of the attempt, denial of further suicidal ideation after the event, and the absence of a suicide note were common findings. Most denied excessive time spent planning. The most common diagnosis in this group was adjustment disorder with depressed mood. Suicide intent scores were not high, inconsistent with the majority of patients being aware of the lethality of the method. CONCLUSION: Sociodemographic findings resemble those of psychological autopsy studies of subjects completing suicide by this method. Survival in this group was due to failure of the method or unexpected discovery rather than patient factors. This population described the method as highly acceptable and accessible emphasising the urgent need for reduction of access to this means of suicide in Australia.     

Involuntary orofacial movements in hospitalised patients with mental handicap or epilepsy: relationship to developmental/intellectual deficit and presence or absence of long-term exposure to neuroleptics.

Among 42 adult patients with mental handicap who had received treatment with neuroleptic drugs, the prevalence of orofacial dyskinesia increased with age and those with such involuntary movements were characterised by a considerably greater degree of mental handicap. Similar associations were found among a group of 15 patients with epilepsy. Two of seven other mentally handicapped patients and one of eight other epileptic patients showed indistinguishable orofacial dyskinesia, despite no record of them having received neuroleptic drugs.     

Physician and patient perceptions of the route of administration of venous thromboembolism prophylaxis: results from an international survey

Introduction

Acceptability of a prescribed treatment regimen is crucial to its clinical success, and the route of drug administration can play an important role in determining acceptability. This international survey explored physician and patient perceptions of injectable and oral treatments, and how these perceptions affect acceptability of treatments. Findings are discussed in the context of patient acceptance of treatments for venous thromboembolism (VTE) management.

Methods

Physicians who are regular prescribers of VTE prophylaxis and a randomly selected patient population were recruited to take part in a questionnaire. Patients had to answer 23 questions and physicians gave their predictions of patients’ responses.

Results

In total, 568 physicians and 825 patients from 5 countries took part in the survey. More patients considered injectable treatments effective than considered oral treatments effective (87% versus 76%, respectively). This trend was well predicted by the physicians (98% and 61%, respectively). Additionally, 46% of patients would accept an injectable treatment program lasting > 2 months (rising to 67% for life-threatening diseases), a figure underestimated by physicians (11% and 46%, respectively). Overall, 73% of patients stated they would never miss an injection, where as 54% of physicians expected patients to miss one injection in a month of therapy.

Conclusions

Physicians who are regular prescribers of VTE prophylaxis underestimate patients’ ability to accept injectable treatments as an alternative to oral therapy. This survey suggests that injectable treatments may be an acceptable, and often preferred, option over oral administration of therapeutic and preventive medicines.     

Brief note: Applying developmental intergroup perspectives to the social ecologies of bullying: Lessons from developmental social psychology

Over the past decades, the field of bullying research has seen dramatic growth, notably with the integration of the social-ecological approach to understanding bullying. Recently, researchers (Hymel et al., 2015; Hawley & Williford, 2015) have called for further extension of the field by incorporating constructs of group processes into our investigation of the social ecologies of bullying. This brief note details the critical connections between power, social identity, group norms, social and moral reasoning about discrimination and victimization, and experiences of, evaluations of, and responses to bullying. The authors highlight a parallel development in the bridging of developmental social-ecological and social psychological perspectives utilized in the field of social exclusion that provides a roadmap for extending the larger field of bullying research.This article is part of a Special Issue entitled [VSI: Bullying] IG000050.     

Teaching students with intellectual or developmental disabilities to write: a review of the literature

The purpose of this review was to identify effective methods for teaching writing to students with intellectual disabilities. After criteria were established, database searches and hand searches of selected peer-reviewed journals were conducted. Findings revealed a relatively small number of studies that met the criteria for inclusion. Participants, settings, research designs, independent variables, dependent variables, and results are synthesized across studies. Writing instruction effects on various written expression outcomes were aggregated by averaging percentage of non-overlapping data (PND) across studies. Findings revealed that strategy instruction was investigated more frequently than other types of approaches. Strategy instruction was consistently found to be very effective for teaching writing skills to students with intellectual disabilities. Limitations, directions for future research, and implications for practice are discussed.     

Immune cell activity during the initial stages of withdrawal from chronic exposure to cocaine or morphine

The immunosuppression accompanying illicit drug use has been shown to contribute to a decreased resistance to a variety of pathogens; however, there is relatively little information on how long these effects persist following withdrawal from chronic drug exposure. To begin to address this question, Sprague-Dawley male rats were administered either cocaine (10 mg/kg, i.p., b.i.d.) for 7 days or morphine (escalating doses up to 40 mg/kg, s.c., b.i.d.) for a 10-day period. Control groups of animals received similar saline injections for equivalent time periods. Drug administration was abruptly discontinued and animals were sacrificed at 2, 24, 72 or 96 h following the last dose. At these time points, proliferation responses of peripheral blood T-lymphocytes stimulated by concanavalin A (Con A) and plasma levels of corticosterone were measured. Plasma corticosterone levels of cocaine- or morphine-treated animals were found to be significantly elevated 24 h following drug cessation as compared to saline animals. At this time, proliferation responses were significantly decreased and were further suppressed during cocaine and morphine withdrawal at 96 and 72 h, respectively. These results suggest that abrupt cessation of cocaine or morphine administration leads to activation of stress-related pathways that may contribute to an increased susceptibility of infection during the initial withdrawal phase.     

Behavioral effects following subacute inhalation exposure to m-xylene or trimethylbenzene in the rat: a comparative study

Trimethylbenzene (TMB), like xylene (dimethylbenzene), is a significant constituent of some industrial solvent mixtures. In earlier studies, we found that in the rat a subacute low-level inhalation exposure to some of the TMB isomers may result in behavioral alterations detectable weeks after the exposure [Neurotoxicol Teratol 19;1997:327; Int J Occup Med Environ Health 11;1998:319]. The purpose of the present study was to compare m-xylene (XYL) and each of the TMB isomers: 1,2,3-TMB (hemimellitene - HM), 1,2,4-TMB (pseudocumene - PS), and 1,3,5-TMB (mesitylene - MES) with respect to the ability for inducing behavioral effects in the rat. The rats (10-11 animals per group) were exposed repeatedly for 4 weeks (6 h per day, 5 days per week) to XYL (XYL group), HM (HM group), PS (PS group) or MES (MES group) at 100 ppm, or sham exposed (C group) in 1.3 cu/m dynamic inhalation chambers. Starting 2 weeks after exposure the following forms of rat's behavior were assessed: radial maze performance, spontaneous activity in an open field, learning and retention of passive and active (two-way) avoidance response, and heat-induced paw licking before and after a 2 min footshock (a test for assessment of the stress response). None of the solvent-exposed groups differed considerably from the control one with respect to the radial maze performance. Compared to control rats, the rats of the XYL, PS and MES groups, but not those of HM group, showed a significantly higher spontaneous locomotor activity in the open field, an impaired passive avoidance learning and significantly longer paw-lick latencies 24 h after footshock. Acquisition, but not retention, of the two-way active avoidance response was significantly impaired in all solvent-exposed groups. The XYL group did not differ significantly from PS, MES or HM group in any of the behavioral parameters. The above results show that a short-term exposure to any of the TMB isomers or m-xylene at concentration as low as 100 ppm may induce persistent behavioral alterations in the rat.     

Levodopa absorption profile in Parkinson's disease: Evidence to indicate qualitative difference from the control

In this study the authors report levodopa absorption profiles in eight patients with early stage Parkinson's disease (PD) and in eight age-matched normal control (NC) subjects; the gastric emptying time (GET) was studied simultaneously. Patients with PD showed a significantly higher peak plasma levodopa concentration, however, no significant difference in the GET was present between the two groups; therefore, the higher plasma levodopa peak could not be ascribed to the difference in the GET. In the NC subjects, plasma peak levodopa level was positively correlated with the GET, however, an inverse correlation was observed in the PD patients, suggesting the presence of a qualitative difference in the levodopa absorption mechanism between early PD and the normal population. Enhanced levodopa absorption may be a useful early marker for PD.     

Topographic distribution of efferent fibers originating from homotopic or heterotopic transplants: heterotopically transplanted neurons retain some of the developmental characteristics corresponding to their site of origin

The present study was undertaken to determine whether the topographical distribution of cortical efferents is exclusively dependent on environmental cues or is also controlled by intrinsic factors. For that purpose, we used a sensitive tract tracing method (Phaseolus vulgaris leucoagglutinin) to compare the pattern of efferent fibers of homotopic and heterotopic transplants of embryonic (E16) neocortex. Our findings indicate that transplants of embryonic sensorimotor cortex placed homotopically in the sensorimotor cortex of newborn rats distribute a set of efferent projections not fundamentally different from that of normal sensorimotor cortex. The pattern of efferents arising from transplants of embryonic occipital cortex heterotopically placed in the sensorimotor cortex of newborns is strikingly different. Heterotopically transplanted neurons: (i) only rarely contact normal targets of the motor cortex; (ii) systematically project towards normal targets of the visual cortex (primary and secondary visual cortical areas, dorsal and ventral lateral geniculate nuclei, lateral dorsal and lateral posterior thalamic nuclei, anterior pretectal nucleus and superficial and intermediate layers of the superior colliculus); (iii) distribute fibers to structures normally receiving fibers from both motor and visual cortices (caudate-putamen, pontine nuclei), either exclusively into the visual cortico-recipient zone of the structure or into both visual and motor cortico-recipient zones. Taken together, these results seem to indicate that the heterotopically transplanted cells have retained certain anatomical characteristics of their locus of origin.