Neurobehavioral Effects Research Articles

Endocrine-Disrupting Chemicals Exposure Alter Neuroendocrine Factors, Disrupt Cardiac Functions and Provokes Hypoxia Conditions in Zebrafish Model.

Zebrafish (Danio rerio) is an increasingly popular vertebrate model used for assessing the toxicity of endocrine-disrupting chemicals (EDCs) on living beings. The zebrafish features high genetic homology to mammals, because of its rapid embryonic development, optical transparency of phenotypic screening embryos, high throughput genetic and chemical screening which make them a powerful toxicological model. This systematic review aimed to assess the recent literature on the use of zebrafish model in EDCs toxicity studies. We capture the data on the types of EDCs used, zebrafish life stages associated with the toxicity, and its effects on the alterations in neuroendocrine factors and cardiac hypoxia in zebrafish. A total of 17 articles published between 2010 and 2020 were curated. The information gathered highlighted the association of EDCs with cardiological outcomes and neurobehavioral effects and distorted expression of genes. The genes that were highlighted in the paper include bdnf, ntrk2a, grin2cb, VTG-1, HIF-1α, tnnt2, ntrk1, and pax6b. The effect of EDCs on cardiac hypoxia and neurodevelopmental and behavioral factors of zebrafish were described in all the papers chosen for this review. The involvement of EDCs in altered regulation of gene expression can be studied further to identify the potential EDC compounds on its toxicological and endocrine disruption function at the molecular level.

Embryonic exposure to benzo[a]pyrene causes age-dependent behavioral alterations and long-term metabolic dysfunction in zebrafish

Polycyclic aromatic hydrocarbons (PAH) are products of incomplete combustion which are ubiquitous pollutants and constituents of harmful mixtures such as tobacco smoke, petroleum and creosote. Animal studies have shown that these compounds exert developmental toxicity in multiple organ systems, including the nervous system. The relative persistence of or recovery from these effects across the lifespan remain poorly characterized. These studies tested for persistence of neurobehavioral effects in AB* zebrafish exposed 5–120 h post-fertilization to a typical PAH, benzo[a]pyrene (BAP). Study 1 evaluated the neurobehavioral effects of a wide concentration range of BAP (0.02–10 μM) exposures from 5 to 120 hpf during larval (6 days) and adult (6 months) stages of development, while study 2 evaluated neurobehavioral effects of BAP (0.3–3 μM) from 5 to 120 hpf across four stages of development: larval (6 days), adolescence (2.5 months), adulthood (8 months) and late adulthood (14 months). Embryonic BAP exposure caused minimal effects on larval motility, but did cause neurobehavioral changes at later points in life. Embryonic BAP exposure led to nonmonotonic effects on adolescent activity (0.3 μM hyperactive, Study 2), which attenuated with age, as well as startle responses (0.2 μM enhanced, Study 1) at 6 months of age. Similar startle changes were also detected in Study 2 (1.0 μM), though it was observed that the phenotype shifted from reduced pretap activity to enhanced posttap activity from 8 to 14 months of age. Changes in the avoidance (0.02–10 μM, Study 1) and approach (reduced, 0.3 μM, Study 2) of aversive/social cues were also detected, with the latter attenuating from 8 to 14 months of age. Fish from study 2 were maintained into aging (18 months) and evaluated for overall and tissue-specific oxygen consumption to determine whether metabolic processes in the brain and other target organs show altered function in late life based on embryonic PAH toxicity. BAP reduced whole animal oxygen consumption, and overall reductions in total basal, mitochondrial basal, and mitochondrial maximum respiration in target organs, including the brain, liver and heart. The present data show that embryonic BAP exposure can lead to neurobehavioral impairment across the life-span, but that these long-term risks differentially emerge or attenuate as development progresses.

Mechanism of action and neurotoxic effects of chronic exposure to bisphenol F in adult zebrafish

Although bisphenol F (BPF), the main replacement for bisphenol A, has been commonly used in polycarbonate production, its neurotoxicity and the underlying mechanisms remain poorly understood. To address this knowledge gap, this study aimed to assess the neurotoxicity caused by chronic exposure to BPF and to identify its underlying mechanisms. We exposed adult zebrafish chronically to BPF at environmentally relevant concentrations (0.001, 0.01, and 0.1 mg/L) for 4 weeks. The results revealed that with BPF crossing the blood–brain barrier and bioaccumulating in brain tissues, chronic exposure to BPF resulted in anxiety-like behaviors and disruptions in learning and memory function in adult zebrafish. Furthermore, BPF toxicity in the zebrafish brain involved the dysregulation of metabolic pathways for choline and kynurenine in neurotransmitter systems and for 17β-estradiol, cortisol, pregnenolone-sulfate, and Dehydroepiandrosterone (DHEA)-sulfate in neurosteroid systems. RNA-seq analysis revealed that BPF exposure affected metabolic pathways, calcium signaling pathways, neuroactive ligand–receptor interactions, tight junctions, gap junctions, and the gonadotropin-releasing hormone signaling pathway. Our results indicate that chronic exposure to BPF alters the neurochemical profile of the brain and causes neurobehavioral effects, such as anxiety and cognitive decline. Overall, the multimodal approach, including behavioral and neurochemical profiling technologies, has great potential for the comprehensive assessment of potential risks posed by environmental pollutants to human and ecosystem health.

Reproductive and neurobehavioral effects of maternal exposure to dinotefuran in the F1 -generation mice.

Few studies were found on the neurobehavioral toxicity of dinotefuran in mammals. This study was designed to evaluate the reproductive and neurobehavioral effects of maternal exposure to dinotefuran in mice. Dinotefuran was given in the diet at levels of 0% (control), 0.012% (18.2-50.6 mg/kg body weight [bw]/day), 0.03% (44.2-125.8 mg/kg bw/day), and 0.075% (111.3-311.0 mg/kg bw/day) in females (10/group) during the gestation (gestation day 1-5 to 15-19) and lactation periods (lactation day 0 to 24-28). Selected reproductive and neurobehavioral parameters were measured in the F1 generation. Litter size and litter weight significantly increased in the high-dose group. The average body weight of male and female offspring increased in treatment groups at postnatal day (PND) 21. In female offspring, surface righting on PND 4 was delayed in higher-dose groups. Cliff avoidance on PND 7 was delayed in a dose-related trend. The route of olfactory orientation on PND 14 was delayed in the high-dose group. For exploratory behavior of the F1 generation, the frequencies of mice with urination increased in a dose-related trend in male offspring. In female offspring, the related variables of rearing increased in dose-related manners. The average rearing time lengthened and the number of defecations increased in the high-dose group in adult males. In adult females, the rearing time shortened in the high-dose group. Several variables differed in the high-dose group for spontaneous behavior in adult females. The dose levels of dinotefuran produced several adverse effects on neurobehavioral parameters in mice.

Allopurinol attenuates repeated traumatic brain injury in old rats: A preliminary report

Traumatic brain injury (TBI) is an overlooked cause of morbidity, which was shown to accelerate inflammation, oxidative stress, and neuronal cell loss and is associated with spatial learning and memory impairments and some psychiatric disturbances in older adults. However, there is no effective treatment in order to offer a favorable outcome encompassing a good recovery after TBI in older adults. Hence, the present study aimed to investigate the histological and neurobehavioral effects of Allopurinol (ALL) in older rats that received repeated TBI (rTBI). For this purpose, a weight-drop rTBI model was used on old male Wistar rats. Rats received 5 repeated TBI/sham injuries 24 h apart and were treated with saline or Allopurinol 100 mg/kg, i.p. each time. They were randomly assigned to three groups: control group (no injury); rTBI group (received 5 rTBI and treated with saline); rTBI+ALL group (received 5 rTBI and treated with Allopurinol). Then, half of the animals from each group were sacrificed on day 6 and the remaining animals were assessed with Open field, Elevated plus maze and Morris Water Maze test. Basic neurological tasks were evaluated with neurological assessment protocol every other day until after the 19th day from the last injury. Brain sections were processed for neuronal cell count in the hippocampus (CA1), dentate gyrus (DG), and prefrontal cortex (PC). Also, an immunohistochemical assay was performed to determine NeuN, iNOS, and TNFα levels in the brain regions. The number of neurons was markedly reduced in CA1, GD, and PC in rats receiving saline compared to those receiving allopurinol treatment. Immunohistochemical analysis showed marked induction of iNOS and TNFα expression in the brain tissues which were reduced after allopurinol at 6 and 19 days post-injury. Also, ALL-treated rats demonstrated a remarkable induce in NeuN expression, indicating a reduction in rTBI-induced neuronal cell death. In neurobehavioral analyses, time spent in closed arms, in the corner of the open field, swimming latency, and distance were impaired in injured rats; however, all of them were significantly improved by allopurinol therapy.To sum up, this study demonstrated that ALL may mitigate rTBI-induced damage in aged rats, which suggests ALL as a potential therapeutic strategy for the treatment of recurrent TBI.

Cardiotoxicity and neurobehavioral effects induced by acrylamide in Daphnia magna

Acrylamide has neurotoxic and/or cardiotoxic effects on humans however available information regarding the neuro- and cardiotoxicity currently is very limited for freshwater organism models. Using three distinct techniques, thus, we investigated the neuro- and cardiotoxic effects of acrylamide in the freshwater invertebrate model, Daphnia magna. We exposed D. magna to acrylamide at concentrations of 0.3, 2.7, and 11.1 mg/L for 48 h alongside a control group. We then conducted physiological (thoracic limb activity and heart rate) and behavioral tests (including distance moved, velocity, turn angle, moving duration, the distance between subjects, and body contact frequency), as well as gene transcription analyses (related to cardiomyopathy, the serotonergic synapse, neuroactive ligand-receptor interactions, the GABAergic synapse, and acetylcholine receptors). After acrylamide exposure, the thoracic limb activity and heart rates of D. magna showed time- and dose dependent inhibition. From low to high exposure concentrations, both heart rates and thoracic limb activity were decreased. Additionally, the distance between subjects and body contact frequencies was significantly reduced. At the gene transcription level, acrylamide significantly altered the transcription of five genes related to cardiomyopathy and eight genes related to the serotonergic synapse, neuroactive ligand-receptor interactions, and the GABAergic synapse. The signs of hindered neural and cardiac functions were shown in D. magna. This suggests that acrylamide exposure leads to cardiotoxicity and neurobehavior defects in D. magna. Because cardiotoxicity and neurobehavioral changes may cause an ecological imbalance via predation of D. magna, acrylamide may also be considered a threat to freshwater ecosystem.

Neurobehavioral follow-up of children exposed to selective serotonin reuptake inhibitors in utero.

Systematic data regarding long-term neurobehavioral effects of maternal antidepressant use during pregnancy are sparse. The aim of this study was to evaluate the impact of gestational exposure to antidepressants on later neurodevelopmental function. This study describes a cohort of mother-child dyads (44 mothers, 54 children) in which maternal depressive symptoms and medication exposures were prospectively collected across pregnancy and the postpartum period. Children age 6 to 17 were assessed using validated instruments across domains of childhood behavior and executive memory and functioning. No associations were found between maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and atypical neurodevelopment of children. Borderline clinical or clinical ranges of internalizing symptoms were associated with exposure to a higher maternal depressive symptom burden during pregnancy compared with those in the normal range. Compared with age- and sex-matched controls, the SSRI-exposed group showed superior performance on executive function tasks; findings did not demonstrate elevated risk for abnormal neurodevelopment in children age 6 to 17 exposed to SSRIs in utero. Deviations from the norm were instead associated with higher in utero exposure to maternal depression burden. This study highlights the need for rigorous studies of long-term outcomes after fetal antidepressant exposure.

Deadly gun violence, neighborhood collective efficacy, and adolescent neurobehavioral outcomes.

Gun violence is a major public health problem and costs the United States $280 billion annually (1). Although adolescents are disproportionately impacted (e.g. premature death), we know little about how close adolescents live to deadly gun violence incidents and whether such proximity impacts their socioemotional development (2, 3). Moreover, gun violence is likely to shape youth developmental outcomes through biological processes-including functional connectivity within regions of the brain that support emotion processing, salience detection, and physiological stress responses-though little work has examined this hypothesis. Lastly, it is unclear if strong neighborhood social ties can buffer youth from the neurobehavioral effects of gun violence. Within a nationwide birth cohort of 3,444 youth (56% Black, 24% Hispanic) born in large US cities, every additional deadly gun violence incident that occurred within 500 meters of home in the prior year was associated with an increase in behavioral problems by 9.6%, even after accounting for area-level crime and socioeconomic resources. Incidents that occurred closer to a child's home exerted larger effects, and stronger neighborhood social ties offset these associations. In a neuroimaging subsample (N= 164) of the larger cohort, living near more incidents of gun violence and reporting weaker neighborhood social ties were associated with weaker amygdala-prefrontal functional connectivity during socioemotional processing, a pattern previously linked to less effective emotion regulation. Results provide spatially sensitive evidence for gun violence effects on adolescent behavior, a potential mechanism through which risk is biologically embedded, and ways in which positive community factors offset ecological risk.

Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats.

Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic's long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.

Maternal antibiotics disrupt microbiome, behavior, and temperature regulation in unexposed infant mice.

Maternal antibiotic (ABx) exposure can significantly perturb the transfer of microbiota from mother to offspring, resulting in dysbiosis of potential relevance to neurodevelopmental disorders such as autism spectrum disorder (ASD). Studies in rodent models have found long-term neurobehavioral effects in offspring of ABx-treated dams, but ASD-relevant behavior during the early preweaning period has thus far been neglected. Here, we exposed C57BL/6J mouse dams to ABx (5mg/ml neomycin, 1.25μg/ml pimaricin, .075% v/v acetic acid) dissolved in drinking water from gestational day 12 through offspring postnatal day 14. A number of ASD-relevant behaviors were assayed in offspring, including ultrasonic vocalization (USV) production during maternal separation, group huddling in response to cold challenge, and olfactory-guided home orientation. In addition, we obtained measures of thermoregulatory competence in pups during and following behavioral testing. We found a number of behavioral differences in offspring of ABx-treated dams (e.g., modulation of USVs by pup weight, activity while huddling) and provide evidence that some of these behavioral effects can be related to thermoregulatory deficiencies, particularly at younger ages. Our results suggest not only that ABx can disrupt microbiomes, thermoregulation, and behavior, but that metabolic effects may confound the interpretation of behavioral differences observed after early-life ABx exposure.

Association between NMDAR antagonists, drug abuse and dependence: A disproportionality analysis from the WHO pharmacovigilance database.

Ketamine and dextromethorphan are widely abused psychoactive substances. Inhibition of N-methyl-d-aspartate receptors (NMDARs) results in neurobehavioural effects including hallucinations, "out of body" sensations and dissociative effects. However, little is known about a possible extended addictive class effect linked to pharmacologically-related amino-adamantane derivatives (e.g., amantadine and memantine). Using a quasi-Bayesian analytic method, we investigated the potential association between the use of approved NMDAR antagonists (i.e., dextromethorphan, ketamine, amantadine and memantine) and the reporting of drug abuse and dependence in the WHO pharmacovigilance database (VigiBase®), which includes >21 million individual case safety reports collected from >130 countries. This disproportionality analysis identified a significant association for all investigated drugs: dextromethorphan (IC = 3.03 [2.97-3.09]), ketamine (IC = 1.70 [1.57-1.83]), amantadine (IC = 0.21 [0.06-0.35]) and memantine (IC = 0.27 [0.13-0.40]), suggesting a class effect for drug abuse and dependence. This first signal requires further investigations, but health professionals need to be alert to the potential of abuse of NMDAR antagonists, especially in the current "opioid epidemic" context, due to their growing interest as non-opioid antinociceptive drugs.

Rewarded Extinction Increases Amygdalar Connectivity and Stabilizes Long-Term Memory Traces in the vmPFC.

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (CC; a form of rewarded-extinction) to standard extinction at recent (24 h) and remote (approximately one month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-h relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standard-extinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One month later, the retrieval of both standard-extinction and rewarded-extinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-h and one-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans.SIGNIFICANCE STATEMENT Prevalent treatments for pathologic fear and anxiety are based on the principles of Pavlovian extinction. Unfortunately, extinction forms weak memories that only temporarily inhibit the retrieval of threat associations. Thus, to increase the translational relevance of extinction research, it is critical to investigate whether extinction can be augmented to form a more enduring memory, especially after long intervals. Here, we used a multiday fMRI paradigm in humans to compare the short-term and long-term neurobehavioral effects of aversive-to-appetitive counterconditioning (CC), a form of augmented extinction. Our results provide novel evidence that including an appetitive stimulus during extinction can reduce short-term threat relapse and stabilize the memory trace of extinction in the ventromedial prefrontal cortex (vmPFC), for at least one month after learning.

The development, but not expression, of alcohol front-loading in C57BL/6J mice maintained on LabDiet 5001 is abolished by maintenance on Teklad 2920x rodent diet.

Excessive alcohol (ethanol) consumption, such as binge drinking, is extremely commonplace and represents a major health concern. Through modeling excessive drinking in rodents, we are beginning to uncover the neurobiological and neurobehavioral causes and consequences of this pattern of ethanol intake. One important factor for modeling binge drinking in mice is that they reliably drink to blood ethanol concentrations (BECs) of 80 mg/dl or higher. Drinking-in-the-dark (DID) is a commonly used mouse model of binge drinking, and we have shown that this method reliably results in robust ethanol front-loading and binge-level BECs in C57BL/6J (B6) mice and other ethanol-preferring mouse strains/lines. However, establishing the DID model in a new vivarium space forced us to consider the use of rodent diet formulations that we had not previously used. The current set of experiments were designed to investigate the role of two standard rodent diet formulations on binge drinking and the development of ethanol front-loading using DID. We found that BECs in animals maintained on LabDiet 5001 (LD01) were double those found in mice maintained on Teklad 2920x (TL20). Interestingly, this effect was paralleled by differences in the degree of front-loading, such that LD01-fed mice consumed approximately twice as much ethanol in the first 15 min of the 2-h DID sessions as the TL20-fed mice. Surprisingly, however, mice that developed front-loading during maintenance on the LD01 diet continued to display front-loading behavior after being switched to the TL20 diet. These data emphasize the importance of choosing and reporting diet formulations when conducting voluntary drinking studies and support the need for further investigation into the mechanisms behind diet-induced differences in binge drinking, particularly front-loading.

The impact of constitutive mTORC1 hyperactivity on structural synaptic plasticity and social behaviour under standard conditions and environmental enrichment

IntroductionAutism spectrum disorders (ASD) are a group of neurodevelopmental disabilities causing major social, communication, and behavioural challenges. Although causative roles of altered genes and environment are recognized, the underlying mechanisms remain elusive.ObjectivesWe carried out a longitudinal analysis of morphological correlates of synaptic plasticity in the cortex with an array of neuro-behavioural tests in Tsc2 loss-of-function ASD rats with persistent mTORC1 hyperactivity.MethodsDendritic spine density and morphology with astroglial response were analysed along with behavioural tests in 45 d.o., 90 d.o. and 12 m.o. age groups maintained under standard or enriched conditions.ResultsWe report a higher density of spines, with a bigger proportion of thin spines in 90 d. o. Tsc2+/- rats, while under enrichment the spine density in 12 m.o groups was lower. In behavioural tests, rats under enrichment showed higher activity in open arms and anogenital contact tests in the second and third age groups. They also showed enhanced self-grooming. Total distance travelled in the open field by Tsc2+/- rats was less in the first and second age groups. Confocal imaging showed an increase in pS6 expression in second and third Tsc2+/- groups, implying mTORC1 hyperactivity.ConclusionsOur results show that the environment may have differential neuro-behavioural impacts in rats with unleashed mTORC1, in agreement with the two-hit mechanisms of the underlying neuro-behavioural effects in this model. Although the results of the morphometric analysis suggest a causal link between behavioural changes with altered synaptic plasticity, the mechanisms and involved signalling remain to be defined.DisclosureNo significant relationships.

Neurobehavioral assessment of Danio rerio intoxicated by Mercury and the use of Mercurius solubilis

Background: Mercury is used in various industrial. Part of Mercury's industrial waste is discharged into the environment, rivers and their tributaries, thus contaminating aquatic animals. Aim: to evaluate Mercury-induced behavioral changes in Zebrafish (Danio rerio) by the analysis of locomotor activity and parameters related to neurotoxicity and to verify whether ultra-diluted substances can decrease neurobehavioral effects and toxic. Methodology: The fishes were separated into 4 monitoring aquariums with 8 fishes each, with temperature, pH controlled, until the time of the toxicological experiments. 0.5 mL of Mercury 6cH, 30cH and distilled water (positive control) were added per liter of water in each aquarium containing 6 liters of water, then 3 mL of medication per aquarium, the white control received no medication and the toxic agent. After 1 hour the drugs were added, toxic mercury (200 μg/L), 4 mL per aquarium was added and remained so for 24 hours. All the experiment was run in blind, and the drugs identified by codes. The animals were subjected to behavioral tests (Open Field-locomotion; Vertical Open Field for neurotoxicity evaluation and Light and Dark Test), and each stage was recorded for later evaluation of movements and neurobehavioral changes. ANOVA was performed, followed by Tukey test, with p &lt;0.05. Results: Mercury produced an anxiogenic effect in animals that were submitted to it without medication. In the vertical open field, there was an increase in erratic movements (1.25 ± 1.0) and tremors (0.87 ± 0.35) compared to the control (0.12 ± 0.35 and 0.25 ± 0.46 respectively), proving the toxic effect. Fishes which received the medication at 6 cH and 30 ch showed tremors and erratic movements similar to control. Conclusion: 200 μg/L mercury in water can cause neurobehavioral disturbances in fishes, and animals receiving Mercurius 6 cH and 30 cH ultra-diluted drug did not show neurotoxicity.

Occupational risk assessment of organophosphates with an emphasis on psychological and oxidative stress factors.

Organophosphate pesticides (OPPs) are widely used all over the world in domestic and industrial settings, but these chemicals affect the nervous system, induce suicidal thoughts, depression and anxiety, and impair sleep quality. The purpose of this study was to investigate the relationship between the main toxicity mechanisms of OPPs, oxidative stress and cholinesterase inhibition, and psychological parameters in chronic exposure to OPPs. This cross-sectional study was conducted on 56 male OPPs factory workers as the worker group and 47 unexposed individuals within the same age range as the control group. Psychological factors were assessed using validated questionnaires. The activity of plasma cholinesterase and oxidative stress biomarkers, total antioxidant capacity of plasma, lipid peroxidation (LPO), and protein carbonylation were determined in blood samples by spectrophotometer. Sleep quality score in the factory workers was lower, and depression and suicidal ideation scores were higher than those in the control group. These factory workers showed 35% lower levels of plasma cholinesterase activity than did the controls. Compared to the control group, a significant impairment in oxidative stress biomarkers was also observed in the workers. Meanwhile, there was a significant relationship between the duration of employment and the level of LPO as well as a significant correlation between the quality of sleep and plasma cholinesterase in the workers. In conclusion, long-term exposure to OPPs could cause oxidative damages and neurobehavioral effects. The close monitoring of workplace exposure to organophosphates pesticides and also their respective solvents along with the reduction of working hours are of the necessities to avoid the adverse impacts of exposure to these pesticides.

Late Gestation Exposure to PolyI:C‐Induced Maternal Immune Activation Results in Sex‐Dependent Antiviral Responses in Rat Placenta

IntroductionViral infections are a major cause of pregnancy‐related complications and can lead to neurodevelopmental deficits in offspring. Viral infections stimulate maternal immune activation (MIA), which disrupts the delicate immune balance required for pregnancy. The placenta is a temporary organ that forms the interface between mom and baby during pregnancy and provides nutrition and protection for the developing fetus. Placental responses to MIA, and how MIA alters placental function, are not well understood. Polyinosinic:polycytidylic acid (PolyI:C), a synthetic double‐stranded RNA and viral mimetic elicits MIA in rodent models. PolyI:C‐induced MIA is sufficient to cause neurobehavioural consequences in offspring, with male offspring typically exhibiting more severe outcomes than female offspring.ObjectiveThe aim of this project was to elucidate how MIA affects the immunological profiles of the nascent male and female placenta and brain from a late prenatal PolyI:C stimulation.HypothesisWe hypothesize that injection of PolyI:C into pregnant rats at late gestation will induce antiviral responses in the placenta and fetal brain, and these responses will differ between male and female fetuses.MethodsTo test this hypothesis, pregnant Sprague‐Dawley rats were injected intravenously with 4 mg/kg PolyI:C (N = 5) or saline (N = 4) on GD18.5. Five hours after injection, placentas and fetal brains were collected. Quantitative RT‐PCR was used to measure expression of various genes associated with antiviral responses (e.g., Ifna, Il6, Il1a, Il1b, Tnfa, Ido1, Cxcl10, Rsad2, Cxcl11, Ccl5, and Tlr3) in the placenta. A Student’s t‐test was used to compare differences between two means, and a two‐way analysis of variance, followed by Sidak’s post‐hoc analysis was used to compare differences between treatments and sexes. Means were considered statistically significant when P ≤ 0.05.ResultsPolyI:C‐treated male placentas (n = 9) showed significantly higher levels of Rsad2(2.4‐fold), Ifna (2.8‐fold), Mx1(9.4‐fold), and Cxcl10(23.3‐fold) compared to saline‐treated male placentas (n = 8; P ≤ 0.05). PolyI:C‐treated female placentas (n = 10) showed a significant upregulation of Cxcl10(25.4‐fold) and Mx1 (11.4‐fold), as well as of Cxcl11(19.8‐fold) and Tnfa(2.3‐fold) compared to saline‐treated female placentas (n = 8; P ≤ 0.05). Among PolyI:C‐treated samples, male placentas showed significantly increased expression of Ifna when compared to female placentas (2.8‐fold, P ≤ 0.05).ConclusionOur results show that PolyI:C‐induced MIA at late gestation stimulates a robust antiviral response in the placenta, including higher levels of Ifna in male placentas than female placentas.SignificanceFuture work will characterize PolyI:C‐induced antiviral and sex‐dependent responses in fetal brains. Overall, this research will provide further insight into MIA‐induced susceptibility to pregnancy complications and neurodevelopmental outcomes.

Cannabis Use and Neuroadaptation: A Call for Δ 9 -Tetrahydrocannabinol Challenge Studies.

Currently, the assessment of the neurobehavioral consequences of repeated cannabis use is restricted to studies in which brain function of chronic cannabis users is compared to that of non-cannabis using controls. The assumption of such studies is that changes in brain function of chronic users are caused by repeated and prolonged exposure to acute cannabis intoxication. However, differences in brain function between chronic cannabis users and non-users might also arise from confounding factors such as polydrug use, alcohol use, withdrawal, economic status, or lifestyle conditions. We propose a methodology that highlights the relevance of acute Δ9-tetrahydrocannabinol (THC) dosing studies for a direct assessment of neuroadaptations in chronic cannabis users. The approach includes quantification of neurochemical, receptor, and functional brain network changes in response to an acute cannabis challenge, as well as stratification of cannabis using groups ranging from occasional to cannabis-dependent individuals. The methodology allows for an evaluation of THC induced neuroadaptive and neurocognitive changes across cannabis use history, that can inform neurobiological models on reward driven, compulsive cannabis use.

Dexamethasone-Induced Sarcopenia and Physical Frailty in Children With Acute Lymphoblastic Leukemia: Protocol for a Prospective Cohort Study.

BackgroundDuring treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells; however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases.ObjectiveThis study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes.MethodsThis prospective study is being pursued within the framework of the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopenia/frailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopenia/frailty assessment consists of bioimpedance analysis (skeletal muscle mass [SMM]), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG; walking speed), and physical activity questionnaires. To evaluate potential change in sarcopenia/frailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors.ResultsPatient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed.ConclusionsThis first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities. The results will provide knowledge about these complications, the association between dexamethasone treatment and muscle loss and other components of frailty, and therefore insights into the severity of this side effect. By exploring potential determinants that may be associated with sarcopenia and physical frailty, we may be able to identify children at risk at an earlier stage and provide timely interventions.International Registered Report Identifier (IRRID)DERR1-10.2196/33517

Comprehensive insight into the neurotoxic mechanisms of low dose Pb exposure in Wistar rats: Benchmark dose analysis

Lead (Pb) is a toxic metal that affects almost all human's system and organs, with the nervous system as the most sensitive. Better understanding of the Pb neurobehavioral effects and neurotoxicity requires realistic study scenarios based on low level exposure. The aim of this study was to determine neurotoxic effects and mechanisms of Pb in six low doses and to establish dose-response relationship for these effects and related Benchmark dose (BMD). Forty-two, male albino Wistar rats were randomized into seven groups, control and Pb-exposed: 0.1, 0.5, 1, 3, 7 and 15 mg Pb/kg body weight/day (oral gavage) for 28 days. Behavioural tests (Elevated plus maze test, Spontaneous locomotor activity test and Novel object recognition test) were conducted in the last week of experiment, in the control, lower (0.5 mg Pb/kg), middle (3 mg Pb/kg) and higher (15 mg Pb/kg) dose groups. The acetylcholinesterase activity, oxidative status and essential elements levels (Cu, Zn, Mn and Fe) were measured in brain tissue along with histological analyses. External and internal dose-response analyses were performed using PROASTweb 70.1 software. The results have shown that subacute exposure to very low doses of Pb resulted in memory deficits in rats that was accompanied with acetylcholinesterase enzyme activity decrease. The observed hyperactive behaviour was accompanied by dose-dependent induction of brain oxidative stress and Zn elevation. The histological alterations in Purkinje cells were only detected in the group treated with the highest Pb dose. The lowest BMD considering entire oxidative status was calculated based on total oxidative status (4.5e-06 mg Pb/kg b.w./day). The findings reported in our study may be beneficial in further evaluating the health consequences and human health risk assessment of low-level Pb exposure.