Unraveling the Hippocampal Molecular and Cellular Alterations behind Tramadol and Tapentadol Neurobehavioral Toxicity.

Tramadol and tapentadol are chemically related opioids prescribed for the analgesia of moderate to severe pain. Although safer than classical opioids, they are associated with neurotoxicity and behavioral dysfunction, which arise as a concern, considering their central action and growing misuse and abuse. The hippocampal formation is known to participate in memory and learning processes and has been documented to contribute to opioid dependence. Accordingly, the present study assessed molecular and cellular alterations in the hippocampal formation of Wistar rats intraperitoneally administered with 50 mg/kg tramadol or tapentadol for eight alternate days. Alterations were found in serum hydrogen peroxide, cysteine, homocysteine, and dopamine concentrations upon exposure to one or both opioids, as well as in hippocampal 8-hydroxydeoxyguanosine and gene expression levels of a panel of neurotoxicity, neuroinflammation, and neuromodulation biomarkers, assessed through quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of hippocampal formation sections showed increased glial fibrillary acidic protein (GFAP) and decreased cluster of differentiation 11b (CD11b) protein expression, suggesting opioid-induced astrogliosis and microgliosis. Collectively, the results emphasize the hippocampal neuromodulator effects of tramadol and tapentadol, with potential behavioral implications, underlining the need to prescribe and use both opioids cautiously.

Exposure to polystyrene microplastics reduces sociality and brain oxytocin levels through the gut-brain axis in mice.

The rising global prevalence of microplastics (MPs) has highlighted their diverse toxicological effects. The oxytocin (OT) system in mammals, deeply intertwined with social behaviors, is recognized to be vulnerable to environmental stressors. We hypothesized that MP exposure might disrupt this system, a topic not extensively studied. We investigated the effects of MPs on behavioral neuroendocrinology via the gut-brain axis by exposing adolescent male C57BL/6 mice to varied sizes (5 µm and 50 µm) and concentrations (100 µg/L and 1000 µg/L) of polystyrene MPs over 10 weeks. The results demonstrated that exposure to 50 µm MPs significantly reduced colonic mucin production and induced substantial alterations in gut microbiota. Notably, the 50 µm-100 µg/L group showed a significant reduction in OT content within the medial prefrontal cortex and associated deficits in sociality, along with damage to the blood-brain barrier. Importantly, blocking the vagal pathway ameliorated these behavioral impairments, emphasizing the pivotal role of the gut-brain axis in mediating neurobehavioral outcomes. Our findings confirm the toxicity of MPs on sociality and the corresponding neuroendocrine systems, shedding light on the potential hazards and adverse effects of environmental MPs exposure on social behavior and neuroendocrine frameworks in social mammals, including humans.

Environmentally relevant exposure to cotinine induces neurobehavioral toxicity in zebrafish (Danio rerio): A study using neurobehavioral and metabolomic approaches.

As an important psychoactive substance, cotinine is ubiquitous in aquatic environment and poses a threat to aquatic organisms. However, the mechanism of its adverse health impacts remains unclear. We evaluated the effects of cotinine exposure at environmentally relevant concentrations on the development and locomotor behavior of zebrafish (Danio rerio) larvae using neurotransmitters and whole endogenous metabolism. Mild developmental toxicity and significant neurobehavior disorder, such as spontaneous movement (1-1000 µg/L), 48 hpf tactile response (50, 100, and 1000 µg/L), and 144 hpf swimming speed (1, 10, 100, 500, and 1000 µg/L), were observed in zebrafish. Exposure to cotinine led to significant alterations in 11 neurotransmitters, including homogentisic acid, serotonin, glutamic acid and aspartic acid, etc. 298 metabolites were identified and two pathways - linoleic acid metabolism and taurine and hypotaurine metabolism - were delineated. In addition, amino acid neurotransmitters were significantly correlated with metabolites such as arachidonic acid as well as its derivatives, steroidal compounds, and amino acids. Serotonin demonstrates a noteworthy correlation with 31 out of 40 differentially expressed neurotransmitters, encompassing lipids, amino acids, and other compounds. These novel findings contribute to a comprehensive understanding of the ecological risks associated with cotinine contamination in surface waters.

Titanium Dioxide (TiO2) Nanoparticle Toxicity in a Caenorhabditis elegans Model.

Titanium dioxide is a compound that is used in the food, cosmetic, and paint industries; however, it is still toxic to humans and the environment. This study determined the toxicities of titanium dioxide nanoparticles (TiO2 NPs) in a Caenorhabditis elegans (C. elegans) model. The effects of commercially available (C-TiO2) and synthetically (S-TiO2) prepared TiO2 NP solutions on lethality, lifespan, growth, reproduction, locomotion, and gene expression were studied in C. elegans. Exposure to TiO2 NPs (0.0, 0.01, 0.1, 1.0, and 10 mg/L) did not result in any change to the survival rate or body length of the nematodes, regardless of the concentration. However, there was a decrease in the reproduction (brood size) and locomotion (body bending and head thrashing) of the nematodes as the TiO2 NP concentration increased. The longevity of the nematodes was shortened following TiO2 NP exposure. The gene expression of sod-1, sod-3, ctl-1, ctl-2, cyp35A2, mlt-1, and mlt-2 in the nematodes showed that there was an overexpression of all genes when the worms were exposed to 1 mg/L C-TiO2 or 10 mg/L S-TiO2. It was therefore concluded that compared with S-TiO2, C-TiO2 possibly causes more toxicity or genotoxicity in the C. elegans model.

Co-exposure to lead, mercury, and cadmium induces neurobehavioral impairments in mice by interfering with dopaminergic and serotonergic neurotransmission in the striatum.

Humans are exposed to lead (Pb), mercury (Hg), and cadmium (Cd) through various routes, including drinking water, and such exposure can lead to a range of toxicological effects. However, few studies have investigated the toxic effects of exposure to mixtures of metals, particularly in relation to neurotoxicity. In this study, 7-week-old male mice were exposed to Pb, Hg, and Cd individually or in combination through their drinking water for 28 days. The mice exposed to the metal mixture exhibited significantly reduced motor coordination and impaired learning and memory abilities compared to the control group and each of the single metal exposure groups, indicating a higher level of neurotoxicity of the metal mixture. The dopamine content in the striatum was significantly lower in the metal mixture exposure group than in the single metal exposure groups and the control group. Furthermore, compared to the control group, the metal mixture exposure group showed a significantly lower expression level of tyrosine hydroxylase (TH) and significantly higher expression levels of dopamine transporter (DAT), tryptophan hydroxylase 1 (TPH1), and serotonin reuptake transporter (SERT). Notably, there were no significant differences in SERT expression between the single metal exposure groups and the control group, but SERT expression was significantly higher in the metal mixture exposure group than in the single metal and control groups. These findings suggest that the key proteins involved in the synthesis and reuptake of dopamine (TH and DAT, respectively), as well as in the synthesis and reuptake of serotonin (TPH1 and SERT, respectively), play crucial roles in the neurotoxic effects associated with exposure to metal mixtures. In conclusion, this study demonstrates that simultaneous exposure to different metals can impact key enzymes involved in dopaminergic and serotonergic neurotransmission processes, leading to disruptions in dopamine and serotonin homeostasis and consequently a range of detrimental neurobehavioral effects.

Developmental and neurobehavioral toxicity of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) (antioxidant AO2246) during the early life stage of zebrafish.

BACKGROUND: 2,2'-Methylenebis (4-methyl-6-tert-butylphenol) (AO2246) is a synthetic phenolic antioxidant extensively used in food packaging bags and cosmetics. Recently, AO2246 was detected with unexpectedly high concentrations in plasma and breast milk samples from pregnant and lactating women. Hence, it is essential to conduct a thorough investigation to evaluate the detrimental effects of AO2246 on biota. OBJECTIVE: To investigate the developmental and behavioral toxicity of AO2246 in zebrafish, as well as the molecular mechanisms underlying these effects. METHODS: Zebrafish embryos were exposed to AO2246 at concentrations ranging from 0.05 to 10 µM for up to 6 days postfertilization (dpf). Hatching rate, survival rate, heart rate, and body length were measured. Locomotor behavioral and electrophysiologal analyses were performed. Two fluorescence-labeled transgenic zebrafish lines (endothelium-Tg and macrophage/microglia-Tg) were employed. RNA sequencing was carried out. RESULTS: AO2246 has a 96-hour LC50 value of 3 µM. The exposure of AO2246 resulted in a significant reduction in both hatching rate and heart rate. Analysis of locomotor behavior demonstrated that larvae exposed to AO2246 doses exceeding 2 µM exhibited a significant decrease in both total distance and mean velocity. Electrophysiological recordings demonstrated a noteworthy reduction in spike activity at a concentration of 3 µM, relative to control conditions. The administration of AO2246 at 3 µM elicited morphological reactivity and immune alteration of the midbrain microglia in the macrophage/microglia-transgenic zebrafish line, indicating a potential contribution of neurological disorders to behavioral defects. RNA sequencing analysis revealed altered gene expression profiles at high AO2246 concentrations, particularly the dysregulation of pathways associated with neuronal function. CONCLUSIONS: The present study demonstrates that AO2246 exposure elicits developmental and neurobehavioral toxicity in zebrafish larvae. Specifically, exposure to AO2246 was found to cause disturbances in neuronal electrophysiological activity and neurological disorders, which ultimately led to the impairment of locomotor behavior in zebrafish larvae.

Neurotoxicity and behavioral disorders induced in mice by acute exposure to the diamide insecticide chlorantraniliprole.

Diamide insecticides activate ryanodine receptors expressed in lepidopteran skeletal muscle and promote Ca2+ release in the sarcoplasmic reticulum, causing abnormal contractions and paralysis, leading to death of the pest. Although they had been thought not to act on nontarget organisms, including mammals, adverse effects on vertebrates were recently reported, raising concerns about their safety in humans. We investigated the neurotoxicity of the acute no-observed-adverse-effect level of chlorantraniliprole (CAP), a diamide insecticide, in mice using clothianidin (CLO), a neonicotinoid insecticide, as a positive control. The CLO-administered group showed decreased locomotor activities, increased anxiety-like behaviors, and abnormal human-audible vocalizations, while the CAP-administered group showed anxiety-like behaviors but no change in locomotor activities. The CAP-administered group had greater numbers of c-fos-immunoreactive cells in the hippocampal dentate gyrus, and similar to the results in a CLO-administered group in our previous study. Blood corticosterone levels increased in the CLO-administered group but did not change in the CAP-administered group. Additionally, CAP was found to decreased 3-Methoxytyramine and histamine in mice at the time to maximum concentration. These results suggest that CAP-administered mice are less vulnerable to stress than CLO-administered mice, and the first evidence that CAP exposure increases neuronal activity and induces anxiety-like behavior as well as neurotransmitter disturbances in mammals.

Persistent neurobehavioral and neurochemical anomalies in middle-aged rats after maternal diazinon exposure.

Diazinon is an organophosphate pesticide that has a history of wide use. Developmental exposures to organophosphates lead to neurobehavioral changes that emerge early in life and can persist into adulthood. However, preclinical studies have generally evaluated changes through young adulthood, whereas the persistence or progression of deficits into middle age remain poorly understood. The current study evaluated the effects of maternal diazinon exposure on behavior and neurochemistry in middle age, at 1 year postpartum, comparing the results to our previous studies of outcomes at adolescence and in young adulthood (4 months of age) (Hawkey 2020). Female rats received 0, 0.5 or 1.0 mg/kg/day of diazinon via osmotic minipump throughout gestation and into the postpartum period. The offspring were tested on a battery of locomotor, affective, and cognitive tests at young adulthood and during middle age. Some of the neurobehavioral consequences of developmental DZN seen during adolescence and young adulthood faded with continued aging, whereas other neurobehavioral effects emerged with aging. At middle age, the rats showed few locomotor effects, in contrast to the locomotor hyperactivity that had been observed in adolescence. Notably, though, DZN exposure during development impaired reference memory performance in middle-aged males, an effect that had not been seen in the younger animals. Likewise, middle-aged females exposed to DZN showed deficient attentional accuracy, an effect not seen in young adults. Across adulthood, the continued potential for behavioral defects was associated with altered dopaminergic function, characterized by enhanced dopamine utilization that was regionally-selective (striatum but not frontal/parietal cortex). This study shows that the neurobehavioral impairments from maternal low dose exposure to diazinon not only persist, but may continue to evolve as animals enter middle age.

Leachate from plastic food packaging induced reproductive and neurobehavioral toxicity in zebrafish.

The present study mimicked daily life exposure to plastic food package bags and evaluated its effects on the reproductive and neurobehavioral responses using zebrafish model. Gas chromatography-mass spectrometer (GC/MS) full scan analysis revealed that phthalic acid, isobutyl octyl ester (DEHP) and its metabolites were the main leachate from plastic bags. Our results demonstrated that during the eight weeks exposure, leaching from plastic bags treated with boiling water (P-high group) significantly affected the spawn egg production, embryo hatching and larval malformation rate. Cross-spawning trails between zebrafish collected from the controls and P-high group at the end of eight weeks showed that these adverse effects were more severe in the offspring derived from paternal exposure than those derived from the maternal exposure, suggesting leached chemicals may have a more pronounced effect in sperm than in eggs. In addition, P-high group male testis weight, sperm motility and sperm swimming velocities were decreased significantly. After eight weeks treatment, neurobehavioral tests demonstrated significant changes in the swimming speed during free swimming and light-dark stimulation in the adult zebrafish from P-high group, with the effects being more severe in the males than females. P-high group males also showed altered response in the light/dark explore and mirror attacks assays.

The organophosphate insecticide diazinon and aging: Neurobehavioral and mitochondrial effects in zebrafish exposed as embryos or during aging.

Organophosphate (OP) compounds comprise one of the most widely used classes of insecticides worldwide. OPs have been shown to have negative human health impacts, particularly developmental neurotoxicity. However, neurotoxic impacts in later adulthood and during the aging process are relatively uncharacterized. The present study examined diazinon (DZN), an OP, to determine the neurobehavioral consequences, in addition to mitochondrial dysfunction on a macroscale (whole organism basal respiration) and on a microscale (whole organ mitochondrial respiration), using zebrafish (ZF) as a model. One group of 14-month-old adult ZF were exposed acutely as adults (0.4, 1.25, and 4.0 µM) for five days and tested as adults, and another group was exposed developmentally 5-120 h post-fertilization (70, 210, and 700 nM) and tested at larval, adolescent, adult, and aging life stages. ZF exposed acutely as adults did not display many significant neurobehavioral impacts or mitochondrial dysfunction. Conversely, the embryonically exposed ZF showed altered behavioral functions at each stage of life which emerged and attenuated as fish transitioned from each developmental stage to the next. Mitochondrial oxygen consumptions measurement results for developmentally DZN exposed ZF showed significant increases in the low and middle dose groups in organs such as the brain and testes. Overall, there is an indication that early developmental exposure to DZN had continuing adverse neurobehavioral and cellular consequences throughout their lives well into adulthood and aging periods.

Early life stage transient aristolochic acid exposure induces behavioral hyperactivity but not nephrotoxicity in larval zebrafish.

Aristolochic acids (AA) are nitrophenanthrene carboxylic acids found in plants of the Aristolochiaceae family. Humans are exposed to AA by deliberately taking herbal medicines or unintentionally as a result of environmental contamination. AA is notorious for its nephrotoxicity, however, fewer studies explore potential neurotoxicity associated with AA exposure. The developing nervous system is vulnerable to xenobiotics, and pregnant women exposed to AA may put their fetuses at risk. In the present study, we used the embryonic zebrafish model to evaluate the developmental neurotoxicity associated with AA exposure. At non-teratogenic concentrations (≤ 4 µM), continuous AA exposure from 8 to 120 hours post fertilization (hpf) resulted in larval hyperactivity that was characterized by increased moving distance, elevated activity and faster swimming speeds in several behavioral assays. Further analysis revealed that 8-24 hpf is the most sensitive exposure window for AA-induced hyperactivity. AA exposures specifically increased motor neuron proliferation, increased apoptosis in the eye, and resulted in cellular oxidative stress. In addition, AA exposures increased larval eye size and perturbed the expression of vision genes. Our study, for the first time, demonstrates that AA is neurotoxic to the developmental zebrafish with a sensitive window distinct from its well-documented nephrotoxicity.

Bee venom Apis mellifera lamarckii rescues blood brain barrier damage and neurobehavioral changes induced by methyl mercury via regulating tight junction proteins expression in rat cerebellum.

The objective of the current study is to investigate the protective effect of Egyptian bee venom (BV) against methyl mercury chloride (MMC) induced blood-brain barrier (BBB) damage and neurobehavioral changes. Eighty male Sprague-Dawley rats were randomly grouped into 1st control (C), 2nd BV (0.5 mg/kg S/C for14 days), 3rd MMC (6.7 mg/kg orally/14 days), and 4th MMC + BV group. MMC exposure significantly altered rat cognitive behavior, auditory startle habituation, and swimming performance, increased the exploratory, grooming, and stereotypic behavior. MMC significantly impaired BBB integrity via induction of inflammation, oxidative stress, and down-regulation of tight junction proteins genes (TJPs) mRNA expression levels: Occludin (OCC), Claudins-5 (CLDN5), Zonula occludens-1 (ZO-1), while up-regulated the transforming growth factor-beta (TGF-ß) mRNA expression levels. MMC revealed a significantly higher percentage of IgG positive area ratio, a higher index ratio of Iba1, Sox10, and ss-DNA, while index ratio of CD31, neurofilament, and pan neuron showed a significant reduction. Administration of BV significantly regulates the MMC altered behavioral responses, TJPs relative mRNA expression, and the immune-expression markers for specific neural cell types. It could be concluded for the first time that BV retains a promising in vivo protection against MMC-induced BBB dysfunction and neurobehavioral toxicity.

Translating Neurobehavioral Toxicity Across Species From Zebrafish to Rats to Humans: Implications for Risk Assessment.

There is a spectrum of approaches to neurotoxicological science from high-throughput in vitro cell-based assays, through a variety of experimental animal models to human epidemiological and clinical studies. Each level of analysis has its own advantages and limitations. Experimental animal models give essential information for neurobehavioral toxicology, providing cause-and-effect information regarding risks of neurobehavioral dysfunction caused by toxicant exposure. Human epidemiological and clinical studies give the closest information to characterizing human risk, but without randomized treatment of subjects to different toxicant doses can only give information about association between toxicant exposure and neurobehavioral impairment. In vitro methods give much needed high throughput for many chemicals and mixtures but cannot provide information about toxicant impacts on behavioral function. Crucial to the utility of experimental animal model studies is cross-species translation. This is vital for both risk assessment and mechanistic determination. Interspecies extrapolation is important to characterize from experimental animal models to humans and between different experimental animal models. This article reviews the literature concerning extrapolation of neurobehavioral toxicology from established rat models to humans and from zebrafish a newer experimental model to rats. The functions covered include locomotor activity, emotion, and cognition and the neurotoxicants covered include pesticides, metals, drugs of abuse, flame retardants and polycyclic aromatic hydrocarbons. With more complete understanding of the strengths and limitations of interspecies translation, we can better use animal models to protect humans from neurobehavioral toxicity.

Neurobehavioral, physiological and inflammatory impairments in response to bifenthrin intoxication in Oreochromis niloticus fish: Role of dietary supplementation with Petroselinum crispum essential oil.

This study was conceptualized in order to assess the 96-h LC50 of bifenthrin (BF) in O. niloticus and also to measure the biochemical, behavioral, and molecular responses of the fish suchronically exposed to a sub-lethal concentration of the insecticide. The role of Petroselinum crispum essential oil (PEO) supplementation in mitigating the resulted neurotoxic insult was also investigated. The acute toxicity study revealed that the 96-h LC50 of BF is 6.81 µg/L, and varying degrees of behavioral changes were recorded in a dose-dependent manner. The subchronic study revealed reduction of dissolved oxygen and increased ammonia in aquaria of BF-exposed fish. Clinical signs revealed high degree of discomfort and aggressiveness together with reductions in survival rate and body weight gain. The levels of monoamines in brain, and GABA and amino acids in serum were reduced, together with decreased activities of Na+/K+-ATPase and acetylcholine esterases (AchE). The activities of antioxidant enzymes were also diminshed in the brain while oxdative damage and DNA breaks were elevated. Myeloperoxidase (MPO) activity in serum increased with overexpression of the pro-inflammatory cytokines in the brain tissue. BF also upregulated the expression of brain-stress related genes HSP70, Caspase-3 and P53. Supplemention of PEO to BF markedly abrogated the toxic impacts of the insecticide, specially at the high level. These findings demonstrate neuroprotective, antioxidant, genoprotective, anti-inflammatory and antiapoptic effects of PEO in BF-intoxicated fish. Based on these mechanistic insights of PEO, we recommend its use as an invaluable supplement in the fish feed.

Identification of markers of depression and neurotoxicity in pesticide exposed agriculture workers.

Earlier, we reported that chronic exposure to pesticides causes a reduction in the acetylcholinesterase activity and hematological and biochemical alterations in agriculture workers. In continuation with that, the present study aimed to investigate the pesticide-induced neurochemical imbalance and its association with behavior alterations in agricultural workers. A significant increase in depressive symptoms, assessed by the Beck Depression Inventory-II was observed in pesticide exposed workers as compared to the unexposed. A decrease in the level of dopamine in plasma and levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acids, norepinephrine, serotonin, and hydroxyindoleacetic acid in urine was also observed. An increase in the levels of MAO-A and MAO-B has also been observed in these individuals. The decreased levels of neurotransmitters in the blood and urine have been linked with increased levels of MAO and pesticide residues in plasma and urine. Furthermore, these changes were associated with a higher incidence of depression in agricultural workers.

Developmental exposure to lead at environmentally relevant concentrations impaired neurobehavior and NMDAR-dependent BDNF signaling in zebrafish larvae.

Lead (Pb) is one of the predominant heavy metals in e-waste recycling arears and recognized as a notorious environmental neurotoxic substance. However, whether Pb at environmentally relevant concentrations could cause neurobehavioral alteration and even what kind of signaling pathway Pb exposure would disrupt in zebrafish were not fully uncovered. In the present study, 6 h postfertilization (hpf) zebrafish embryos were exposed to Pb at the concentrations of 0, 5, 10, and 20 µg/L until 144 hpf. Then the neurobehavioral indicators including locomotor, turnings and social behaviors, and the expressions of selected genes concerning brain-derived neurotrophic factor (BDNF) signaling were investigated. The results showed that significant changes were obtained under 20 µg/L Pb exposure. The hypoactivity of zebrafish larvae in locomotor and turning behaviors was induced during the dark period, while hyperactivity was observed in a two-fish social assay during the light period. The significantly downregulation of genes encoding BDNF, its receptor TrkB, and N-methyl-D-aspartate glutamate receptor (NMDAR) suggested the involvement of NMDAR-dependent BDNF signaling pathway. Overall, our study demonstrated that developmental exposure to Pb at environmentally relevant concentrations caused obvious neurobehavioral impairment of zebrafish larvae by disrupting the NMDAR-dependent BDNF signaling, which could exert profound ecological consequences in the real environment.

Aspergillus terreus (Trichocomaceae): A Natural, Eco-Friendly Mycoinsecticide for Control of Malaria, Filariasis, Dengue Vectors and Its Toxicity Assessment Against an Aquatic Model Organism Artemia nauplii.

Vector-borne diseases like malaria, filariasis, and dengue are transmitted by mosquitoes and they cause global mortality and morbidity due to an increased resistance against commercial insecticides. The present study was aimed to evaluate the neurobehavioral toxicity, knock-down effect, histopathology, ovicidal, adulticidal, and smoke toxicity effect of Aspergillus terreus extract against three mosquito species, namely Anopheles stephensi, Culex quinquefasciatus, and Aedes aegypti (Diptera: Culicidae). The isolated fungal strain was identified as A. terreus (GenBank accession no: KX694148.1) through morphological and molecular (phylogenetic) analysis. The morphological changes in the treated fourth instar larvae shown the demelanization of cuticle and shrinkage of the internal cuticle of anal papillae. The time duration of extract exposure against the larvae determines the level of toxicity. The extract treated larvae were displayed excitation, violent vertical and horizontal movements with aggressive anal biting behavior as the toxic effect on the neuromuscular system. The results of the biochemical analysis indicated that a decrease in the level of acetylcholinesterase, α-carboxylesterase, and ß-carboxylesterase in extract treated fourth instar larvae of all tested mosquito species. The findings of histopathological investigation shown the disorganization of the abdominal region, mainly in mid, hindgut, and gastric caeca, loss of antenna, lateral hair, caudal hair, upper and lower head hairs in the mycelium extract treated An. stephensi, Cx. quinquefasciatus, and Ae. aegypti. The ovicidal bioassay test results showed the mosquito hatchability percentage was directly related to the concentrations of mycelium extract. Nil hatchability of mosquito eggs was noticed at 500 µg/ml concentration. The adulticidal activity of fungal mycelia ethyl acetate extract resulted in a dose-dependent activity (15 and 30 min recovery periods). The higher concentration of extract (1000 mg/L) acted as a repellent, the adult mosquitoes showed restless movement, uncontrolled/anesthetic flight at last died. The better adulticidal activity was observed in the ethyl acetate extract against An. stephensi, Cx. quinquefasciatus followed by Ae. aegypti with the best score of LD50 and LD90 values and nil mortality was found in the control. The results of smoke toxicity assay of the mycelia extract exhibited significant mortality rate against Ae. aegypti (91%), Cx. quinquefasciatus (89%), and An. stephensi (84%). In addition, the present investigation reported the stability and toxic effects of A. terreus mycelium ethyl acetate extract on Artemia nauplii. The swimming speed (0.88 mm s-1) of A. terreus was reduced with ethyl extract 24 h treatment whereas, the control A. nauplii showed the normal speed of 2.96 mm s-1. Altered behavior and swimming movement were observed in the 8 h A. terreus mycelium extract treated A. nauplii. A pale yellow color substance (metabolites) was found in the mid-gut region of the mycelial extract exposed A. nauplii. The outcome of the present study, suggest that the A. terreus metabolites might serve as an alternative, cost-effective, eco-friendly, and target specific mosquitocidal agent in the future.

Tris (2-butoxyethyl) phosphate affects motor behavior and axonal growth in zebrafish (Danio rerio) larvae.

Tris (2-butoxyethyl) phosphate (TBOEP) is an environmental contaminant that poses serious risks to aquatic organisms and their associated ecosystem. Recently, the reproductive and developmental toxicology of TBOEP has been reported. However, fewer studies have assessed the neurotoxic effects in zebrafish (Danio rerio) larvae. In this study, zebrafish embryos were subjected to waterborne exposure of TBOEP at 0, 50, 500, 1500 and 2500 µg/L from 2 to 144-h post-fertilization (hpf). Behavioral measurements showed that TBOEP exposure reduced embryonic spontaneous movement and decreased swimming speed of larvae in response to dark stimulation. In accordance with these motor effects, TBOEP treatment reduced neuron-specific GFP expression in transgenic Tg (HuC-GFP) zebrafish larvae and inhibited the growth of secondary motoneurons, as well as decreased expression of marker genes related to central nervous system development in TBOEP treated group. Furthermore, increased concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as reduction of SOD activity were detected in TBOEP exposure group. The present results showed that the alteration in motor neuron and oxidative stress could together lead to the motor behavior alterations induced by TBOEP.

Overview of Neurotoxicology.

The nervous system has a central and primary function in the body, and its relevance and complexity make it a target for a large number of toxic substances. The most common forms of neurotoxicity are the death of neurons (neuronopathy), the degeneration of axons (axonopathy), damage to glial cells (e.g., myelinopathy), and interference with the axonal membrane or neurotransmission. Important neurotoxicants are found among pesticides, metals, solvents, natural substances, and industrial chemicals. Environmental chemicals may also contribute to the etiopathogenesis of neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Specific testing guidelines exist to assess potential neurotoxicity and developmental neurotoxicity in particular, and novel alternative testing approaches are being developed. © 2017 by John Wiley & Sons, Inc.

Effects of Dechlorane Plus exposure on axonal growth, musculature and motor behavior in embryo-larval zebrafish.

Developmental neurobehavioral toxicity of Dechlorane Plus (DP) was investigated using the embryo-larval stages of zebrafish (Danio rerio). Normal fertilized embryos were waterborne exposed to DP at 15, 30, 60 µg/L beginning from 6 h post-fertilization (hpf). Larval teratology, motor activity, motoneuron axonal growth and muscle morphology were assessed at different developmental stages. Results showed that DP exposure significantly altered embryonic spontaneous movement, reduced touch-induced movement and free-swimming speed and decreased swimming speed of larvae in response to dark stimulation. These changes occurred at DP doses that resulted no significant teratogenesis in zebrafish. Interestingly, in accord with these behavioral anomalies, DP exposure significantly inhibited axonal growth of primary motoneuron and induced apoptotic cell death and lesions in the muscle fibers of zebrafish. Furthermore, DP exposure at 30 µg/L and 60 µg/L significantly increased reactive oxygen species (ROS) and malondialdehyde (MDA) formation, as well as the mRNA transcript levels of apoptosis-related genes bax and caspase-3. Together, our data indicate that DP induced neurobehavioral deficits may result from combined effects of altered neuronal connectivity and muscle injuries.