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This article explores the clinical implications of withdrawal syndromes associated with antidepressant drugs. The author shares their own clinical observations and proposes an oppositional model of tolerance to explain the loss of treatment effectiveness and the occurrence of side effects over time. The article also discusses the phenomenon of withdrawal syndromes during the tapering and discontinuation of antidepressants, emphasizing the need for personalized approaches and the potential for severe and persistent symptoms. The author suggests the use of clonazepam, a medication with neuroprotective properties, to support patients during this phase, and highlights the importance of self-therapy and psychotherapeutic strategies in the discontinuation process. The author calls for further research on the behavioral toxicity of antidepressant medications and emphasizes the importance of individualized treatment approaches. [Extracted from the article]

The marijuana legalization trend in the U.S. will likely lead to increased use by younger adults during gestation and postpartum. The current study examined the hypothesis that delta-9-tetrahydrocannabinol (THC) would disrupt voluntary maternal care behaviors and negatively impact offspring development. Rat dams were gavaged with 0, 2, 5, or 10 mg/kg THC from the 1st day of gestation through the 21st postnatal day. Somatic growth and developmental milestones were measured in the offspring, and maternal pup retrieval tests were conducted on postnatal days 1, 3, and 5. THC did not affect body growth but produced transient delays in the righting reflex and eye opening in offspring. However, there was significant pup mortality due to impaired maternal care. Dams in all THC groups took significantly longer to retrieve their pups to the nest and often failed to retrieve any pups. Serum levels of THC and metabolites measured at this time were comparable to those in breastfeeding women who are chronic users. Benchmark doses associated with a 10% reduction of pup retrieval or increased pup mortality were 0.383 (BMDL 0.228) and 0.794 (BMDL 0.442) mg/kg THC, respectively. The current findings indicate that maternal care is an important and heretofore overlooked index of THC behavioral toxicity and should be included in future assessments of THC's health risks. [ABSTRACT FROM AUTHOR]

There is growing evidence of negative impacts of antidepressants on behavior of aquatic non-target organisms. Accurate environmental risk assessment requires an understanding of whether antidepressants with similar modes of action have consistent negative impacts. Here, we tested the effect of acute exposure to two antidepressants, fluoxetine and venlafaxine (0–50 µg/L), on the behavior of non-target organism, i.e., freshwater pond snail, Lymnaea stagnalis. As compounds interact with chemical cues in the aquatic ecosystems, we also tested whether the effects altered in the presence of bile extract containing 5α-cyprinol sulfate (5α-CPS), a characterized kairomone of a natural predator, common carp (Cyprinus carpio). Behavior was studied using automated tracking and analysis of various locomotion parameters of L. stagnalis. Our results suggest that there are differences in the effects on locomotion upon exposure to venlafaxine and fluoxetine. We found strong evidence for a non-monotonic dose response on venlafaxine exposure, whereas fluoxetine only showed weak evidence of altered locomotion for a specific concentration. Combined exposure to compounds and 5α-CPS reduced the intensity of effects observed in the absence of 5α-CPS, possibly due to reduced bioavailability of the compounds. The results highlight the need for acknowledging different mechanisms of action among antidepressants while investigating their environmental risks. In addition, our results underline the importance of reporting non-significant effects and acknowledging individual variation in behavior for environmental risk assessment. [ABSTRACT FROM AUTHOR]

The marijuana legalization trend in the U.S. will likely lead to increased use by younger adults during gestation and postpartum. The current study examined the hypothesis that delta-9-tetrahydrocannabinol (THC) would disrupt voluntary maternal care behaviors and negatively impact offspring development. Rat dams were gavaged with 0, 2, 5, or 10 mg/kg THC from the 1st day of gestation through the 21st postnatal day. Somatic growth and developmental milestones were measured in the offspring, and maternal pup retrieval tests were conducted on postnatal days 1, 3, and 5. THC did not affect body growth but produced transient delays in the righting reflex and eye opening in offspring. However, there was significant pup mortality due to impaired maternal care. Dams in all THC groups took significantly longer to retrieve their pups to the nest and often failed to retrieve any pups. Serum levels of THC and metabolites measured at this time were comparable to those in breastfeeding women who are chronic users. Benchmark doses associated with a 10% reduction of pup retrieval or increased pup mortality were 0.383 (BMDL 0.228) and 0.794 (BMDL 0.442) mg/kg THC, respectively. The current findings indicate that maternal care is an important and heretofore overlooked index of THC behavioral toxicity and should be included in future assessments of THC’s health risks.

Use of fish as biological early warning indicator for ecological hazards of water pollutants is efficient and fast. However, there is still a lack of attempts to apply fish shoaling behavior to biological early warning. Herein, cluster score was used to evaluate and quantify shoaling behavior of rare minnow ( Gobiocypris rarus) in their health state. Combined with the results of 24 h acute toxicity exposure experiment, the response of rare minnow shoaling behavior to Cd2+, MS222 and p-chloroaniline was tested by gradient exposure experiment and burst pollu- tion simulation experiment. The results showed that rare minnow had obvious shoaling behavior with a cluster score between 3 and 5, which changed significantly when exposed to chemicals. The LOEC values of shoaling behavior of rare minnow exposed to Cd2+, MS222 and p-chloroaniline for 1 h were 3, 11 and 10 mg·L-1, respective- ly. The shoaling behavior of rare minnow was sensitive to the chemical reaction and showed obvious response within 10 min after exposure to the three chemicals. Therefore, cluster score is an excellent quantitative parameter of fish shoaling score, and the shoaling behavior of rare minnow is a great indicator of biological early warning. [ABSTRACT FROM AUTHOR]

The present study examined the effects of environmentally realistic exposure to atrazine (ATZ) on the behavior of sailfin mollies, Poecilia latipinna. ATZ is one of the most commonly used pesticides in the US and a known endocrine disrupting chemical (EDC). The behavior of sailfin mollies is well documented in the scientific literature. Moreover, they are ecologically important indicators of environmental health, widely distributed among the mangroves along the Gulf Coast of the Southeastern US where significant amounts of ATZ are introduced via runoff and storm water drainage from coastal households, businesses, and farms. Four sets of experiments designed to assess ATZ's impact on various aspects of male and female reproductive behavior, aggression, anxiety, and boldness were conducted following 12 weeks of exposure to 1 or 15 ppb water-borne ATZ, along with a no-exposure control group. Results indicated that the behavior of ATZ-exposed individuals differed from those of controls: ATZ exposure affected which stimulus fish (a male vs. a female) subject females preferred to associate with while also affecting female strength of preference for males of larger body size and their sexual receptivity to conspecific males in general. ATZ-exposed males also showed reduced overall responsiveness to conspecific stimuli and directed significantly less aggression toward their mirror image compared with controls. Finally, ATZ exposure affected multiple aspects of male and female behavior that are often used as proxies for boldness and anxiety. Overall, ATZ exposure resulted in alterations across a variety of behaviors attributed to sexual receptivity, mate choice and motivation to mate, aggression, as well as boldness and anxiety. These ATZ-induced behavioral changes may adversely affect the long-term health of natural populations exposed to similar, environmentally realistic concentrations and add to a growing body of empirical data demonstrating substantial fitness consequences of exposure to sublethal concentrations of this known EDC. [ABSTRACT FROM AUTHOR]

The effect of Justicia extensa leaf (ethanolic) extract on behavior and histopathology of Clarias gariepinus fingerling was investigated in the present study. The fish specimens were exposed to graded acute concentrations of the plant leaf extract (0.0, 4.0, 6.0, 8.0, 10.0, and 12.0 mL) for 96 h, during which time-dependent (24 h, 48 h, 72 h, 96 h) lethal concentrations of J. extensa, behavior, and histopathological changes in the gill and liver of the grouped specimens were evaluated. Based on the study findings, the respective values; 10.90, 8.60, 7.00 and 6.80 mL were obtained as the 24, 48, 72 and 96 h median lethal concentrations of J. extensa leaf extract to C. gariepinus fingerling. The study further indicate that the plant affected water quality conditions of the test media in a concentration-dependent manner, except for pH. Consequently, J. extensa elicited prominent behavioral aberrations (excessive mucus secretion, air gulping, respiratory distress, erratic swimming and vertical erection) and induced histopathological lesions in the gill (hyperplasia, erosion, fusion and disorganization of secondary lamella, desquamation and cellular degeneration) and liver (hepatic coagulative necrosis, vacuolation of parenchyma, hyperplasia, necrotic hepatocytes and hepatopancreatic tissue lysis) of C. gariepinus after 96 h exposure duration. The use of plant piscicides for fishing should be applied with caution in order to avert catastrophic events in the aquatic ecosystems.

Fluoroquinolones (FQs) and tetracyclines (TCs), the two β-diketone antibiotics (DKAs), are two frequently detected pollutants in the environment; however, little data are available on their combined toxicity to zebrafish (Danio rerio). This study reports that toxicologic effects of combined DKA (FQs-TCs) exposure on zebrafish were comparable with or slightly less than those of TCs alone, showing that TCs played a major toxicologic role in the mixtures. The effects of FQs, TCs, and DKAs on malformation rates of zebrafish were dose dependent, with EC50 values of 481.3, 16.4, and 135.1 mg/L, respectively. According to the combined effects of DKAs on zebrafish hatching, mortality, and malformation rates, the interaction between FQs and TCs was shown to be antagonistic based on three assessment methods: Toxic Unit, Additional Index, and Mixture Toxic Index. The 1.56 mg/L TC and 9.38 mg/L DKA treatments resulted in higher zebrafish basal swimming rate compared with the control group at 120 hours postfertilization (hpf). in both light and light-to-dark photoperiod experiments. Under conditions of no obvious abnormality in cardiac development, the heart beats were decreased significantly because of DKA exposure, such as decreasing by ∼20% at 150 mg/L DKAs. Transmission electron microscopy observation of myocytes from DKA-exposed hearts displayed prominent interruptions and myofibrillar disorganization of the normal parallel alignment of thick and thin filaments, and partial edematous and dissolved membranes of cell nuclear tissues. At 90 mg/L DKAs, the transcriptional levels of the acta1a, myl7, and gle1b genes, related to heart development and skeletal muscle formation, were significantly changed. This is consistent with the swimming behavior and histopathologic results obtained by transmission electron microscopy. In summary, the toxicity of the combined DKAs to zebrafish was comparable with or less than that of TCs alone and had the ability to impair individual behaviors that are of great importance in the assessment of their ecologic fitness. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 736-750, 2016.

With the appreciation that behavior represents the integration and complexity of the nervous system, neurobehavioral phenotyping and assessment has seen a renaissance over the last couple of decades, resulting in a robust database on rodent performance within various testing paradigms, possible associations with human disorders, and therapeutic interventions. The interchange of data across behavior and other test modalities and multiple model systems has advanced our understanding of fundamental biology and mechanisms associated with normal functions and alterations in the nervous system. While there is a demonstrated value and power of neurobehavioral assessments for examining alterations due to genetic manipulations, maternal factors, early development environment, the applied use of behavior to assess environmental neurotoxicity continues to come under question as to whether behavior represents a sensitive endpoint for assessment. Why is rodent behavior a sensitive tool to the neuroscientist and yet, not when used in pre-clinical or chemical neurotoxicity studies? Applying new paradigms and evidence on the biological basis of behavior to neurobehavioral testing requires expertise and refinement of how such experiments are conducted to minimize variability and maximize information. This review presents relevant issues of methods used to conduct such test, sources of variability, experimental design, data analysis, interpretation, and reporting. It presents beneficial and critical limitations as they translate to the in vivo environment and considers the need to integrate across disciplines for the best value. It proposes that a refinement of behavioral assessments and understanding of subtle pronounced differences will facilitate the integration of data obtained across multiple approaches and to address issues of translation.

The eco-risk of roxarsone (ROX) was evaluated using multiple responses of earthworm biomarkers under different ROX concentrations for 28 d. With the increasing total arsenic accumulation (TAs-E), biological responses in earthworm generally showed a two-stage changes of homeostasis dysregulation and dose-dependent alterations. At the early periods, ROX stress increased the reactive oxygen species (ROS) and lipid peroxidation (LPO) in a similar manner, and apparently disrupted mitochondrial calcium ([Ca2+]m). But earthworms regulated their mitochondrial and redox homeostasis through stable mitochondrial membrane potential (MMP) and increase of ATP level, superoxide dismutase (SOD) and catalase (CAT). After 14 d, the positively correlated mitochondrial effects of ROS, [Ca2+]m, MMP and ATP were related to the behavioral inhibition of burrow length, depth and reuse rate as well as antioxidant up-regulation of Nrf2, HO-1, sod1 and cat. These results contributed possible biomarkers from the dose-dependent relationship between mitochondrial, antioxidant and behavioral responses. Multiple biological detection in earthworms can better reflect the sub-chronic ecotoxicity of phenylarsenic pollutants in soil.

Numerous byproducts resulting from chlorinated disinfection are constantly being generated during water treatment processes. The potential risks of these new emerging pollutions remain largely unknown. Here, we determined the risks of chlorinated disinfection byproducts of diazepam (DZP) in the cellular and zebrafish exposure experiments. The cytotoxicity of disinfection byproducts (MACB and MBCC) was greater than DZP in macrophage raw 264.7 cells at 10 mg/L. We further found that the effects of MBCC on the metabolism of glycine, serine, threonine and riboflavin were far greater than DZP by the targeted metabolomics methods. Moreover, MBCC significantly decreased the peak amplitude of neuronal action potential in primary embryonic rat (Spragu-Dawley SD) hippocampal neurons. We finally determined behavioral toxicity of DZP and byproducts in zebrafish larvae. MBCC significantly decreased the maximal swim-activity and peak duration of zebrafish after 72 h exposure. Altogether, these findings indicate the MBCC pose serious pressures on public health.

Disrupted behavior and respiratory distress effects of 96-h acute deltamethrin exposures in adult Mozambique tilapia, Oreochromis mossambicus, were investigated using behavioral indices and opercular movement, respectively. Deltamethrin concentrations were found to be associated with toxicological (lethal and sublethal) responses. At 24, 48, 72, and 96 h, the LC50 values and 95% confidence limits were 12.290 (11.174–14.411 µg/L), 12.671 (11.334–15.649 µg/L), 10.172 (9.310–11.193 µg/L), and 8.639 (7.860–9.417 µg/L), respectively. The GUTS-model analysis showed that GUTS-SD (stochastic death) with a narrow tolerance distribution in deltamethrin exposed O. mossambicus populations was more sensitive than the GUTS-IT (individual tolerance) model. Prior to death, exposed fish demonstrated concentration-dependent mortality and disturbed behavioral responses, including uncoordinated swim motions, increased mucus secretion, unbalanced and unpredictable swimming patterns, and inactivity. The altered behavioral patterns and increased opercular movement with increased deltamethrin levels and exposure time are strongly suggestive of neurotoxicity and respiratory distress, respectively. Adverse Outcome Pathways (AOPs), describing biological mechanisms and plausible pathways, highlighted oxidative stress and cholinergic effects as intermediate steps linked to respiratory distress and behavioral toxicity.

Non-target organisms in aquatic environments may experience lethal or sublethal effects following exposure to contaminants. Most protocols and regulations, however, are designed to provide protection from lethal effects and are thus based on conventional estimates of population lethality. The relative lack of reliable behavioral endpoints makes it challenging to implement regulations that are similarly protective against sublethal toxicity. The objective of this study was to quantify the avoidance behavior of Hyalella azteca when exposed to three insecticides—bifenthrin (B), chlorpyrifos (C), and permethrin (P)—at a range of estimated lethal concentrations. A two-choice behavioral arena was used for each chemical to quantify H. azteca activity and time spent in either uncontaminated sediment or sediment spiked at concentrations reflecting estimated 48-h lethal concentrations (LC 50 , LC 25 , and LC 10). For all three insecticides, naïve H. azteca demonstrated a preference for the uncontaminated sediment over the contaminated sediment at the LC 50 (B: 312 ng/g OC ; C: 1265 ng/g OC ; P: 5042 ng/g OC) and LC 25 (B: 230 ng/g OC ; C: 859 ng/g OC ; P: 3817 ng/g OC), spending significantly more time in the uncontaminated side of the arena. H. azteca did not avoid sediment at LC 10 (B: 204 ng/g OC ; C: 609 ng/g OC ; P: 1515 ng/g OC) levels, indicating the existence of a potential threshold of detection. Despite the lack of substrate preference at this exposure level, H. azteca were nevertheless more active (i.e., increased zone-switching) when exposed to bifenthrin at the LC 10 , suggesting a possible irritation response (e.g., movement after exposure) to this chemical. Our results provide evidence that H. azteca exhibit innate avoidance responses to sediments contaminated with common insecticides at concentrations below those represented by traditional toxicological endpoints (e.g., LC 50). The sensitivity and ease with which this behavioral endpoint can be assayed demonstrates the potential utility of behavioral endpoints in toxicological assessments using model organisms. [Display omitted] • Avoidance behavior is a sensitive endpoint with population-level consequences. • Hyalella azteca avoided insecticides in sediment at and below the LC 50 and LC 25. • Avoidance was not detected at insecticide concentrations equal to the LC 10. • Increased activity at the bifenthrin LC 10 suggest a threshold of detection. • We advocate for the utility of avoidance as an informative behavioral endpoint. [ABSTRACT FROM AUTHOR]

Keywords: suicidality; Black Box; activation syndrome; behavioral toxicity; antidepressants EN suicidality Black Box activation syndrome behavioral toxicity antidepressants 1 3 3 05/05/20 20200430 NES 200430 In a recent issue of Frontiers in Psychiatry, Spielmans et al. ([1]) defend the 2004 decision of the Food and Drug Administration (FDA) to issue a Black Box warning on the potential risk of suicidality in youth being administered antidepressant medications. As various neural correlates (e.g., amygdala connectivity) have predicted attenuated antidepressant treatment response ([9], [10]), it is possible that such developmental alterations in brain maturation also relate to increased possibility of SSRI-induced behavioral side effects. [Extracted from the article]

This study examined the effects on neurobehavioral function of exposure to low-level mercury vapor (Hg0), methylmercury (MeHg) in female mice and the combination of Hg0 and MeHg during postnatal development. Postnatal mice were exposed to Hg0 at a mean concentration of 0.188 mg/m3 Hg0 and supplied with food containing 3.85 μg/g of MeHg from day 2 to day 28 after delivery. The combined exposure group was exposed to both Hg0 and MeHg, using the same procedure. When their offspring reached the age of 11 weeks, behavioral analyses were performed. The behavioral effects in mice were evaluated based on locomotive activity and rate of center entries in the open field (OPF), learning activity in the passive avoidance response (PA) and spatial learning ability in the radial maze (RM). Total locomotive activity in the OPF significantly decreased in the Hg0, MeHg and combined exposure groups compared with the control group. The proportion of entries to central area in the OPF was significantly higher in the combined exposure group than in the control group, while those in the Hg0 or MeHg exposure group did not differ from the control group. Other behavioral tests did not reveal significant differences among the groups. Behavioral anomalies were more distinctive after combined exposure compared to Hg0 or MeHg exposure alone. The brain Hg concentration of offspring, immediately after exposure, was highest in the combined exposure group, exceeding 2 μg/g, followed by the MeHg and Hg0 exposure groups. Thus, the enhancement of neurobehavioral effects in the combined exposure group was associated with higher brain mercury concentration. [ABSTRACT FROM AUTHOR]

Galantamine hydrobromide and (−)huperzine A, centrally active reversible acetylcholinesterase inhibitors, are potentially superior to the current standard, pyridostigmine bromide, as a pretreatment for organophosphorus chemical warfare nerve agent intoxication. Galantamine, huperzine, and pyridostigmine were compared for time course of acetylcholinesterase inhibition in 12 cynomolgus macaques. Although both galantamine and huperzine shared a similar time course profile for acetylcholinesterase inhibition, huperzine was 88 times more potent than galantamine. The dose for 50% acetylcholinesterase inhibition (ID) was 4.1 ug/kg for huperzine, 362 ug/kg for galantamine, and 30.9 ug/kg for pyridostigmine. In a safety assessment, galantamine, huperzine, and pyridostigmine were examined using an operant time-estimation task. Huperzine and pyridostigmine were devoid of behavioral toxicity, whereas galantamine was behaviorally toxic at doses producing peak acetylcholinesterase inhibition of about 50% and higher. Following pretreatment with galantamine, huperzine or pyridostigmine, monkeys were challenged with the median lethal dose of soman at the time of peak acetylcholinesterase inhibition and evaluated for overt signs of soman toxicity (cholinergic crisis, convulsions). Both huperzine and galantamine were equally effective at preventing overt signs of soman toxicity, but neither drug was capable of preventing soman-induced neurobehavioral disruption. In contrast, three of four pyridostigmine-pretreated animals exposed to soman exhibited convulsions and required therapy. Full functional recovery required 3-16 days. The degree of acetylcholinesterase inhibition was lower for pyridostigmine, but rates of recovery of acetylcholinesterase activity following soman challenge were comparable for all drug pretreatments. Huperzine may be the more promising centrally active reversible acetylcholinesterase inhibitor due to its greater potency and superior safety profile. [ABSTRACT FROM AUTHOR]

The aim of this critical review was to outline emerging trends and perspectives of clinical pharmacopsychology, an area of clinical psychology that is concerned with the psychological effects of medications. The historical development of clinical pharmacopsychology is outlined, with discussion of its most representative expressions and reference to current challenges of clinical research, with particular reference to clinimetrics. The domains of clinical pharmacopsychology encompass the clinical benefits of psychotropic drugs, the characteristics that predict responsiveness to treatment, the vulnerabilities induced by treatment (side effects, behavioral toxicity, iatrogenic comorbidity), and the interactions between drug treatment and psychological variables. Its aim is to provide a comprehensive assessment of the clinical important changes that are concerned with (a) wanted and expected treatment effects, (b) treatment-induced unwanted side effects, and (c) the patient's own personal experience of a change in terms of well-being and/or quality of life. Clinical pharmacopsychology offers a unifying framework for the understanding of clinical phenomena in medical and psychiatric settings. Research in this area deserves high priority. [ABSTRACT FROM AUTHOR]

The frequent detection of progestins in various aquatic environments and their potential endocrine disruptive effects in fish have attracted increasing attention worldwide. However, data on their effects on thyroid function and neurotoxicity in fish are limited, and the underlying mechanisms remain unclear. Here, the effects of gestodene (GES, a common progestin) on the thyroid endocrine and nervous systems of mosquitofish (Gambusia affinis) were studied. Adult female fish were exposed to GES at environmentally relevant concentrations (4.4–378.7 ng/L) for 60 days. The results showed that exposure to 378.7 ng/L GES caused a significant decrease in fish growth compared with the control and a marked reduction in the total distance traveled (50.6%) and swimming velocity (40.1–61.9%). The triiodothyronine (T3) levels were significantly increased by GES in a dose-dependent manner, whereas those of tetraiodothyronine (T4) were significantly decreased only at the G500 concentration. The acetylcholinesterase (AChE) activity was decreased significantly in the 4.42 ng/L GES treatments, but increased significantly at 378.67 ng/L. In the brain, a strong increase in the transcriptional levels of bdnf , trh , and dio2 was observed in fish after the 378.7 ng/L treatment. In addition, chronic exposure to GES caused colloid depletion with a concentration-dependent manner in the thyroid, and angiectasis, congestion, and vacuolar necrosis in the brain. These findings provide a better understanding of the effects of GES and associated underlying mechanisms in G. affinis. [Display omitted] • The effects of gestodene exposure on thyroid endocrine disruption and neurotoxicity were investigated in G. affinis. • The levels of thyroid hormone T3 was increased, while T4 was decreased in G. affinis. • Gestodene caused colloid depletion in the thyroid, and angiectasis, congestion and vacuolar necrosis in the cerebellum. [ABSTRACT FROM AUTHOR]

Mercury (Hg) is a ubiquitous environmental contaminant and potent neurotoxin. In aquatic environments, Hg can be transformed into methylmercury (MeHg), which bioaccumulates in aquatic food webs, including fish. Methylmercury has been shown to transfer from female fish to developing eggs; however, relatively little is known regarding the effects of maternally transferred MeHg on fish embryos. The present study evaluated the effects of maternally transferred MeHg on fathead minnow ( Pimephales promelas) embryos. Embryos were collected from adult fatheads exposed for 30 d to 1 of 3 diets spiked with MeHg: a control diet (0.02 ppm Hg dry wt), a low diet (0.87 ppm Hg dry wt), or a high diet (5.5 ppm Hg dry wt). No effects on spawning frequency, clutch size, or total egg output were observed. In embryos, Hg concentration was a function of female diet and the duration (number of days) of female exposure. Compared with controls, embryos from the low-diet treatment displayed altered embryonic movement patterns (hyperactivity) and decreased time to hatch. Embryos from the high-diet treatment had delayed hatching and increased mortality compared with the other treatments. Collectively, these results suggest that maternally transferred Hg may impact survival, behavior, and developmental milestones of the embryo-larval stages of fish. Environ Toxicol Chem 2016;35:1436-1441. © 2015 SETAC [ABSTRACT FROM AUTHOR]

ABSTRACT Fluoroquinolones (FQs) and tetracyclines (TCs), the two β-diketone antibiotics (DKAs), are two frequently detected pollutants in the environment; however, little data are available on their combined toxicity to zebrafish ( Danio rerio). This study reports that toxicologic effects of combined DKA (FQs-TCs) exposure on zebrafish were comparable with or slightly less than those of TCs alone, showing that TCs played a major toxicologic role in the mixtures. The effects of FQs, TCs, and DKAs on malformation rates of zebrafish were dose dependent, with EC50 values of 481.3, 16.4, and 135.1 mg/L, respectively. According to the combined effects of DKAs on zebrafish hatching, mortality, and malformation rates, the interaction between FQs and TCs was shown to be antagonistic based on three assessment methods: Toxic Unit, Additional Index, and Mixture Toxic Index. The 1.56 mg/L TC and 9.38 mg/L DKA treatments resulted in higher zebrafish basal swimming rate compared with the control group at 120 hours postfertilization (hpf). in both light and light-to-dark photoperiod experiments. Under conditions of no obvious abnormality in cardiac development, the heart beats were decreased significantly because of DKA exposure, such as decreasing by ∼20% at 150 mg/L DKAs. Transmission electron microscopy observation of myocytes from DKA-exposed hearts displayed prominent interruptions and myofibrillar disorganization of the normal parallel alignment of thick and thin filaments, and partial edematous and dissolved membranes of cell nuclear tissues. At 90 mg/L DKAs, the transcriptional levels of the acta1a, myl7, and gle1b genes, related to heart development and skeletal muscle formation, were significantly changed. This is consistent with the swimming behavior and histopathologic results obtained by transmission electron microscopy. In summary, the toxicity of the combined DKAs to zebrafish was comparable with or less than that of TCs alone and had the ability to impair individual behaviors that are of great importance in the assessment of their ecologic fitness. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 736-750, 2016. [ABSTRACT FROM AUTHOR]

Aquatic animals are exposed to various cyanobacterial products released concomitantly to the environment by decaying blooms. Although there exist results on the toxicity of cyanobacterial extracts little is known on the influence of pure oligopeptides or their mixtures and elucidated mechanisms of behavioral toxicity in zooplanktonic organisms. Therefore, the aim of the present study was to assess the effects of single and mixed pure cyanobacterial oligopeptides: microginin FR-1 (MG-FR1), anabaenopeptin-A (ANA-A) and microcystin-LR (MC-LR) at various concentrations on the swimming behavior and catecholamine neurotransmitter activity, muscular F-actin structure, DNA nuclear content and cell viability of a model rotifer Brachionus calyciflorus. Swimming behavior was analyzed with the use of video digital analysis. Fluorescent microscopy imaging was used to analyze neuromotoric biomarkers in the whole organisms: neuromediator release (by staining with EC517 probe), muscle F-actin filaments (by staining with blue phalloidin dye). DNA content and cytotoxicity was also determined by Hoechst 34580 and propidium iodide double staining, respectively. The results showed that single oligopeptides inhibited all the tested endpoints. The binary mixtures induced synergistic interaction on swimming speed except for MG-FR1 +MC-LR which was nearly additive. Both binary and ternary mixtures also synergistically degraded F-actin and triggered cytotoxic effects visible in the whole organisms. Antagonistic inhibitory effects of all the binary mixtures were found on catecholamine neurotransmitter activity, however the ternary mixture induced additive toxicity. Antagonistic effects of both binary and ternary mixtures were also noted on nuclear DNA content. The results of the study suggest that both depression of neurotransmission and impairment of muscle F-actin structure in muscles may contribute to mechanisms of Brachionus swimming speed inhibition by the tested single cyanobacterial oligopeptides and their mixtures. The study also showed that natural exposure of rotifers to mixtures of these cyanobacterial metabolites may result in different level of interactive toxicity with antagonistic, additive synergistic effects depending on the variants and concentrations present in the environment. [Display omitted] • Microginin-FR-1, anabaenopeptin-A-, microcystin-LR affect Brachionus calyciflorus. • Synergistic decrease of swimming speed, muscular F-actin degradation by cyanopeptides. • Antagonistic DNA degradation, decreased neurotransmitter activity by cyanopeptides. • Peptide behavioral toxicity results from neurotransmitter and muscle disorders. [ABSTRACT FROM AUTHOR]

The present study investigated the developmental neurotoxicity of an early exposure to α-HBCDD through the ingestion of contaminated hen's egg in pregnant and lactating Wistar female rats. Hens were given α-HBCDD-contaminated feed (40 ng/g fresh matter) for 5 and 10 days, which produced eggs with HBCDD content of 33 and 102 ng/g lipid weight, respectively. Female rats were administered daily p.o. with an appropriate volume of the whole egg from the day of fertilization (GD0) to the weaning day for pups (PND21). Fetuses and pups were thus exposed continuously to α-HBCDD via the dam over a whole 42-day period that included both gestation and lactation. The administered egg volume was calculated on the basis of daily egg consumption in humans (0.7 egg/person/day) and duration of gestation and lactation in both species, which led animals to be exposed to α-HBCDD at levels of 22 and 66 ng/kg/day, respectively. Neurobehavioral development of pups was investigated from PND3 to PND25 using various tasks including the righting reflex (PND4), the grasping reflex (PND5), the negative geotaxis (PND9), the forelimb grip strength test (PND10) and the locomotor coordination test (PND20). Pup ultrasonic vocalizations were also recorded daily from PND4 to PND14. After weaning, behaviors related to spontaneous locomotor activity and anxiety were examined in the open-field (PND25) and in an elevated-plus maze (PND26), respectively. The results showed a significant decrease in body weight of pups exposed to the lower HBCDD level from PND3 to PND28, whereas the weight of rat pups given 66 ng/kg/day of HBCDD was not different from controls. During the first 3 weeks of life, impairments in motor maturation of pups were observed in a dose-dependent manner depending on the test, whereas no significant differences were reported between male and female pups. At PND26, the anxiety level of female rats exposed to the lowest dose of HBCDD (22 ng/kg/day) was significantly reduced whereas it remained unchanged in males. No significant variations were measured in rats exposed to the higher level of HBCDD (66 ng/kg/day). These results suggest the potent developmental neurotoxicity of an early chronic exposure to the HBCDD α-isomer through the ingestion of hen's eggs contaminated with this pollutant and question the long-lasting consequences of this exposure on behavior abilities and brain functioning in adulthood. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is an environmental endocrine disrupter (EED). Previous studies by our group showed that pre- and postnatal administration of low-level BPA induced depression-like behavior in rats. In this study, we evaluated the effects of prenatal BPA on behavioral responses to a predator odor by using a novel cross-form apparatus consisting of 4 plastic chambers. On the first day, nothing was placed into the chambers (Session 1). On the second day, a predator odor (fox odor) was located in separate chambers at 2 opposite corners of the apparatus (Session 2). Pregnant Wistar rats were exposed to low-dose BPA (less than the reference dose) during the 7 days just before birth, and the offspring of the treated rats were evaluated as adults. The locomotor activity and avoidance response of each rat on both test days were compared. The control and BPA groups showed reduced locomotor activity in the presence of the predator odor, but the odor-avoidance response was significant only in the BPA rats. The BPA-exposed rats were obviously sensitive to the predator odor. These results suggest that prenatal BPA exposure has an amplifying effect on avoidance responses to predator odor stress. [ABSTRACT FROM AUTHOR]

Humans are increasingly and consistently exposed to a variety of endocrine disrupting chemicals (EDCs), chemicals that have been linked to neurobehavioral disorders such as ADHD and autism. Many of such EDCs have been shown to adversely influence brain mesocorticolimbic systems raising the potential for cumulative toxicity. As such, understanding the effects of developmental exposure to mixtures of EDCs is critical to public health protection. Consequently, this study compared the effects of a mixture of four EDCs to their effects alone to examine potential for enhanced toxicity, using behavioral domains and paradigms known to be mediated by mesocorticolimbic circuits (fixed interval (FI) schedule controlled behavior, novel object recognition memory and locomotor activity) in offspring of pregnant mice that had been exposed to vehicle or relatively low doses of four EDCs, atrazine (ATR – 10 mg/kg), perfluorooctanoic acid (PFOA – 0.1 mg/kg), bisphenol-A (BPA – 50 μg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD – 0.25 μg/kg) alone or combined in a mixture (MIX), from gestational day 7 until weaning. EDC-treated males maintained significantly higher horizontal activity levels across three testing sessions, indicative of delayed habituation, whereas no effects were found in females. Statistically significant effects of MIX were seen in males, but not females, in the form of increased FI response rates, in contrast to reductions in response rate with ATR, BPA and TCDD, and reduced short term memory in the novel object recognition paradigm. MIX also reversed the typically lower neophobia levels of males compared to females. With respect to individual EDCs, TCDD produced notable increases in FI response rates in females, and PFOA significantly increased ambulatory locomotor activity in males. Collectively, these findings show the potential for enhanced behavioral effects of EDC mixtures in males and underscore the need for animal studies to fully investigate mixtures, including chemicals that converge on common physiological substrates to examine potential mechanisms of toxicity with full dose effect curves to assist in interpretations of relevant mechanisms. [ABSTRACT FROM AUTHOR]

Disrupted behavior and respiratory distress effects of 96-h acute deltamethrin exposures in adult Mozambique tilapia, Oreochromis mossambicus , were investigated using behavioral indices and opercular movement, respectively. Deltamethrin concentrations were found to be associated with toxicological (lethal and sublethal) responses. At 24, 48, 72, and 96 h, the LC50 values and 95% confidence limits were 12.290 (11.174-14.411 µg/L), 12.671 (11.334-15.649 µg/L), 10.172 (9.310-11.193 µg/L), and 8.639 (7.860-9.417 µg/L), respectively. The GUTS-model analysis showed that GUTS-SD (stochastic death) with a narrow tolerance distribution in deltamethrin exposed O. mossambicus populations was more sensitive than the GUTS-IT (individual tolerance) model. Prior to death, exposed fish demonstrated concentration-dependent mortality and disturbed behavioral responses, including uncoordinated swim motions, increased mucus secretion, unbalanced and unpredictable swimming patterns, and inactivity. The altered behavioral patterns and increased opercular movement with increased deltamethrin levels and exposure time are strongly suggestive of neurotoxicity and respiratory distress, respectively. Adverse Outcome Pathways (AOPs), describing biological mechanisms and plausible pathways, highlighted oxidative stress and cholinergic effects as intermediate steps linked to respiratory distress and behavioral toxicity., Competing Interests: The authors declare no conflict of interest.

Based on laboratory studies under controlled conditions, we have appraised the toxicological impact of dead leaf leachate from four angiosperm species: Populus nigra, Salix babylonica, Acer monspessulanum and Platanus acerifolia, as well as dead needles of a gymnosperm species, Taxus baccata, on the quality of water of Vittel spring (Tizguit, Ifrane region). The results show that at 25° C the toxicity changes with the duration of leaching, the initial concentration, type of treatment of leaves and dead needles and leaf species. Lethal toxicity tests conducted on Artemia salina larvae and fry of Gambusia affinis show that the If and Saule are the most toxic of water ventilated. [ABSTRACT FROM AUTHOR]

Abstract: Exposure of iminodipropionitrile (IDPN) to rodents produces permanent behavioral syndrome characterized by repetitive head movements, circling and back walking. Other synthetic nitriles of industrial importance such as crotonitrile and allylnitrile are also able to produce similar motor deficits in experimental animals. However, due to the well-defined behavioral deficits and their easy quantification, IDPN-induced behavioral syndrome is a preferential animal model to test the interaction of various agents with synthetic nitriles. This study reports the effect of non-specific nitric oxide synthase inhibitor, N-nitro-l-arginine (NARG) on IDPN-induced neurobehavioral toxicity in adult male Wistar rats. Four groups of animals were given i.p. injections of IDPN (100mg/kg) for 6 days. These rats were treated with oral administration of NARG in the doses of 0 (IDPN alone group), 50, 150 and 300mg/kg, 60min before IDPN, respectively. Control rats received vehicle only, whereas another group was treated with 300mg/kg of NARG alone (without IDPN). The results showed that NARG significantly exacerbated the incidence and intensity of IDPN-induced dyskinetic head movements, circling and back walking. The histology of inner ear showed massive degeneration of the sensory hair cells in the crista ampullaris of rats receiving the combined treatment with IDPN and NARG, suggesting a possible role of nitric oxide in IDPN-induced neurobehavioral syndrome in rats. [Copyright &y& Elsevier]

Abstract: Cadmium selenium (CdSe) quantum dots (QDs) are semiconductor nanocrystals that hold wide range of applications and substantial production volumes. Due to unique composition and nanoscale properties, their potential toxicity to aquatic organisms has increasingly gained a great amount of interest. However, the impact of CdSe QDs exposure on zebrafish embryo and larvae remains almost unknown. Therefore, the lab study was performed to determine the developmental and behavioral toxicities to zebrafish under continuous exposure to low level CdSe QDs (0.05–31.25mgL−1) coated with mercaptopropionic acid (MPA). The results showed MPA–CdSe exposure from embryo to larvae stage affected overall fitness. Our findings for the first time revealed that: (1) The 120h LC50 of MPA–CdSe for zebrafish was 1.98mgL−1; (2) embryos exposed to MPA–CdSe resulted in malformations incidence and lower hatch rate; (3) abnormal vascular of FLI-1 transgenic zebrafish larvae appeared after exposure to MPA–CdSe including vascular junction, bifurcation, crossing and particle appearance; (4) larvae behavior assessment showed during MPA–CdSe exposure a rapid transition from light-to-dark elicited a similar, brief burst and a higher basal swimming rate; (5) MPA–CdSe induced embryos cell apoptosis in the head and tail region. Results of the observations provide a basic understanding of MPA–CdSe toxicity to aquatic organisms and suggest the need for additional research to identify the toxicological mechanism. [Copyright &y& Elsevier]

Abstract: CdTe quantum dots (QDs) are nanocrystals of unique composition and properties that have found many new commercial applications; therefore, their potential toxicity to aquatic organisms has become a hot research topic. The lab study was performed to determine the developmental and behavioral toxicities to zebrafish under continuous exposure to low concentrations of CdTe QDs (1–400nM) coated with thioglycolic acid (TGA). The results show: (1) the 120h LC50 of 185.9nM, (2) the lower hatch rate and body length, more malformations, and less heart beat and swimming speed of the exposed zebrafish, (3) the brief burst and a higher basal swimming rate of the exposed zebrafish larvae during a rapid transition from light-to-dark, and (4) the vascular hyperplasia, vascular bifurcation, vascular crossing and turbulence of the exposed FLI-1 transgenic zebrafish larvae. [Copyright &y& Elsevier]

Abstract: This paper provides a summary of the “state of knowledge” regarding behavioral impacts of domoic acid exposure on fish. Initial studies by authors of this paper suggested that fish are behaviorally impacted by domoic acid in the same way that birds and mammals are impacted during toxic Pseudo-nitzschia blooms. However, subsequent research and field observations have contradicted that hypothesis and provide evidence that fish are more tolerant to domoic acid under ecologically relevant exposure conditions than their piscivorous predators. This is an important distinction as more attention has been drawn to domoic acid producing algal blooms and the potential for domoic acid to cause fish kills. Currently available data indicate that domoic acid producing algal blooms do not cause fish kills or neuroexcitotoxic behaviors in fish. Neuroexcitatory behavioral effects have been documented in fish in laboratory studies when fish were intraceolomically (IC) injected with domoic acid. In fact, with IC injection as the mode of exposure all fish, bird, and mammal species tested to date show a similar neurologic sensitivity to domoic acid in terms of behavioral excitotoxicity as quantified by a 50% effective concentration (EC50) metric. However, IC injection is not an ecologically relevant mode of exposure. Dietary consumption during toxic blooms is the route of exposure for fish. Results from oral exposure experiments and observations from multiple highly toxic bloom events have provided strong evidence that fish are not behaviorally affected by domoic acid during natural bloom conditions, even though fish regularly contain high levels of the toxin and act as vectors to seabirds and marine mammals. Collectively, the data presented in this review suggest that fish are not significantly impacted by domoic acid during typical toxigenic Pseudo-nitzschia blooms. [Copyright &y& Elsevier]

BSTRACT Cadmium, a toxic heavy metal with various applications in technology, can affect people both by environmental (foodborne) and occupational (inhalation) exposure and can cause nervous system damage. To model this, rats were subacutely treated either with CdCl2 solution per os (3.0 mg kg−1 b.w.) or nanoparticulate CdO2 (particle size ca 65 nm) by intratracheal instillation (0.04 mg kg−1 b.w.) alone or in sequential combination. Nervous system effects were observed at different levels of function (open field behavior, cortical electrical activity, nerve action potential) and some general toxicological indicators were also measured. Three weeks of oral plus one week of intratracheal exposure caused significant reduction of body weight gain and open field motility. Lengthening of latency of sensory evoked potentials, observed in all treated rats, was also the most significant in the group receiving oral plus intratracheal treatment. Conduction velocity of the tail nerve was likewise decreased in all treated groups. Several of the effects pointed to a potentiating interaction between the two forms of Cd. Modeling environmental and occupational Cd exposure by oral and intratracheal application in rats was feasible, with results suggesting serious negative health effects in humans suffering such a combined exposure. [ABSTRACT FROM AUTHOR]

Abstract: This study investigated the possible effects of a commonly used foliar herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) formulation on medulla spinalis of lebistes. Fish were exposed to 2,4-D (15, 30, 45mgL−1), behavioral changes were monitored. Fish were fixed, histopathological examination was carried out on sections taken from the upper parts of the fish body. Histopathology showed increase in neuronal loss, swelling indicating formation of intracellular edema, vacuolization noticed as the formation of vacuoles within or adjacent to cells, deformation in the Nissl granules, pyknosis and gliosis in medulla spinalis. Behavioral changes were decreased general activity, grouping, shortness in breath, sudden rotations and jumping, loss of equilibrium and colour. In conclusion, this commercial formulation of 2,4-D is considerably neurotoxic to lebistes. Fish constitute the last link in the chain of the feeding cycle in aquatic eco-system, number of studies investigating acute and chronic neurotoxicity of various herbicides in fish should be increased. [Copyright &y& Elsevier]

The eco-risk of roxarsone (ROX) was evaluated using multiple responses of earthworm biomarkers under different ROX concentrations for 28 d. With the increasing total arsenic accumulation (TAs-E), biological responses in earthworm generally showed a two-stage changes of homeostasis dysregulation and dose-dependent alterations. At the early periods, ROX stress increased the reactive oxygen species (ROS) and lipid peroxidation (LPO) in a similar manner, and apparently disrupted mitochondrial calcium ([Ca2+] m). But earthworms regulated their mitochondrial and redox homeostasis through stable mitochondrial membrane potential (MMP) and increase of ATP level, superoxide dismutase (SOD) and catalase (CAT). After 14 d, the positively correlated mitochondrial effects of ROS, [Ca2+] m , MMP and ATP were related to the behavioral inhibition of burrow length, depth and reuse rate as well as antioxidant up-regulation of Nrf2, HO-1, sod1 and cat. These results contributed possible biomarkers from the dose-dependent relationship between mitochondrial, antioxidant and behavioral responses. Multiple biological detection in earthworms can better reflect the sub-chronic ecotoxicity of phenylarsenic pollutants in soil. [Display omitted] ● Bioenergetic, burrowing and antioxidant responses in earthworm are related. ● Mitochondrial calcium, membrane potential and ATP are sensitive biomarkers. ● Gene expression of antioxidases reflect ROX stress more directly than enzymes. [ABSTRACT FROM AUTHOR]

This study addressed the anticonvulsant effects of repeated administration of phenytoin, carbamazepine, phenobarbital, valproate, and ethosuximide in kindled guinea-pigs in order to further substantiate this novel model of partial seizures for the screening of future anticonvulsant drugs. Behavioral toxic effects were assessed at 30 min following drug administration using scores on a sedation/muscle relaxation rating index. In response to suprathreshold stimulation, the anticonvulsant efficacy of the drugs were evaluated from measurements of afterdischarge duration (ADD) and behavioral seizure severity (SS) during a repeated drug treatment schedule in kindled guinea-pigs. All drugs exerted slight to moderate sedative effects in guinea-pigs on our rating index. We found that phenytoin, carbamazepine, and phenobarbital exhibited effective anticonvulsant properties in kindled guinea-pigs by reducing both ADD and SS. We found that valproate consistently reduced ADD throughout the treatment schedule but failed to significantly reduce SS. Lastly, ethosuximide failed to exhibit effective anticonvulsant properties. Our results indicate that the guinea-pig kindling model correctly predicted the actions of these common anticonvulsant drugs in the treatment of partial seizures. Guinea-pig amygdala kindling appears to serve as a useful and valid model for partial epilepsy. [ABSTRACT FROM AUTHOR]

Abstract: Pregnant rhesus monkeys (Macaca mulatta) were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 30 and 300ng/kg by subcutaneous injection at gestational day 20, followed by additional injections of TCDD (1.5 and 15ng/kg, respectively) every 30 days till 90 days after parturition. The offspring delivered from these experimentally TCDD-exposed mothers were subjected to a series of behavioral tests after the weaning at 12–14 months old (MO): a finger maze learning task (12–15MO), encounter tests between two monkeys (at 12–15 and 24–27MO), and an eye-contact test (23–26MO) to estimate learning ability, social interaction with a peer subject, and interest or hostility to a human observer, respectively. TCDD exposure had no significant effect on learning ability or interest/hostility to an observer. It did, however, significantly affect behavioral characteristics in the encounter tests. In the first encounter test, monkeys exposed to TCDD showed more visual exploration and mutual proximity but less stereotypy behavior compared to control monkeys. In the second encounter test, these differences seemed to disappear, suggesting that the behavioral effects of TCDD exposure in the encounter tests might disappear as the monkey develops. This study produced evidence of the behavioral toxicity of TCDD in social interactions using non-human primates. [Copyright &y& Elsevier]