Edward Levin - Academia.edu (original) (raw)
Papers by Edward Levin
Neurotoxicology and Teratology, 2011
Neurotoxicology and Teratology, 2011
control and MeOH males (24.5 g-31.2 g). There were no significant differences in sperm concentrat... more control and MeOH males (24.5 g-31.2 g). There were no significant differences in sperm concentration (1100-1669 × 10 6 /ml), motility (81.3%-87.9%) or normal morphology (84.0%-96.3%) between groups. However, there was a significant linear trend for increased sperm mediated oocyte activation (63.8%-85.0%) with increasing MeOH exposure (χ 2 = 5.60, p = 0.02). There was no significant difference in ovarian or uterine weight between groups (0.25 g-0.39 g and 3.75-6.08 g, respectively). There was a significant linear trend for a decrease in IVM rate with increasing MeOH exposure (χ 2 = 7.53, p = 0.006) attributed to Metaphase I arrest. IVM rates were significantly lower in the 1800 ppm group compared with the control (39.5% v. 27.8%). While there was no effect of MeOH exposure on serum AMH (5.79-13.57 ng/ml) a positive correlation existed between serum AMH and the total number of oocytes retrieved and the total number of mature oocytes post-IVM (r = 0.15-0.19, t = 3.26-5.15, n = 19, p < 0.05). While these findings suggest that there is no overt effect on gonadal morphology, gamete function may be adversely affected in females following FME.
Neurotoxicology and Teratology, 2011
NeuroToxicology, 2017
Background-Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants until the ... more Background-Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants until the early 2000s, mainly in home furnishings and electronics. The persistence of PBDEs in the environment leads to continued ubiquitous exposure to low levels, with infants and children experiencing higher exposures than adults. Accumulating evidence suggest that low-level exposures during early life stages can affect brain development and lead to long-term behavioral impairments. We investigated the effects of zebrafish exposure to low doses of the two prominent PBDEs; 2,2',4,4',5,-Pentabromodiphenyl ether (BDE-99) and 2,2',4,4',-Tetrabromodiphenyl ether (BDE-47), during embryo-development on short-and long-term behavioral endpoints. We included the organophosphate pesticide chlorpyrifos (CPF) due to its well documented neurotoxicity across species from zebrafish to humans. Methods-Zebrafish embryos were exposed to the following individual treatments; 0.1% DMSO (vehicle control); 0.3 µM CPF; 0.01, 0.03, 0.1, 0.3 µM BDE-47; 0.003, 0.03, 0.3, 1, 3, 10, 20 µM BDE-99 from 5 until 120 hours post fertilization (hpf). Low exposure levels were determined as those not causing immediate overt toxicity, and behavior assays were conducted in the low-level range. At 144 hpf the larvae were tested for locomotor activity. At approximately 6 months of age adult zebrafish were tested in a behavioral battery including assays for anxiety-related behavior, sensorimotor response and habituation, social interaction, and predator avoidance. Results-In the short-term, larval locomotor activity was reduced in larvae treated with 0.3 µM CPF and 0.1 µM BDE-47. BDE-99 treatment caused non-monotonic dose effects, with 0.3 µM *
Neurotoxicology and Teratology, 2015
BACKGROUND-FireMaster® 550 (FM 550) is the second most commonly used flame retardant (FR) product... more BACKGROUND-FireMaster® 550 (FM 550) is the second most commonly used flame retardant (FR) product in consumer goods and has been detected in household dust samples. However, neurobehavioral effects associated with exposure have not been characterized in detail. We investigated the behavioral effects of FM 550 in zebrafish to facilitate the integration of the cellular and molecular effects of FM 550 with its behavioral consequences. The effects of developmental FM 550 exposure on zebrafish larvae swimming shortly after the end of exposure as well as the persisting effects of this exposure on adolescent behavior were studied. In addition, the acute effects of FM 550 on behavior with exposure during adolescence in zebrafish were studied. METHODS-Developmental exposure to 0, 0.01, 0.1 or 1 mg/L of FM 550 via immersion spanned 0-5 days post fertilization, with larval testing on day 6 and adolescent testing on days 40-45. Acute adolescent (45 dpf) exposure was to 0, 1.0 or 3.0 mg/L of FM 550 via immersion, for 24 hrs, with testing 2 hr or 1 week later. The vehicle condition was colony tank water with .0004% (developmental) or .0012% (adolescent) DMSO. Zebrafish behavior was characterized across several domains including learning, social affiliation, sensorimotor function, predator escape, and novel environment exploration. RESULTS-Persisting effects of developmental FM 550 exposure included a significant (p < 0.01) reduction in social behavior among all dose groups. Acute FM550 exposure during adolescence caused hypoactivity and reduced social behavior (p's < 0.05) when the fish were tested 2 hr after exposure. These effects were attenuated at the 1 week post exposure testing point. DISCUSSION-Taken together, these data indicate that FM 550 may cause persisting neurobehavioral alterations to social behavior in the absence of perturbations along other
Neurotoxicology and teratology, Jan 13, 2015
Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants that are widely detected... more Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants that are widely detected in the environment, biota, and humans. In mammals, PBDEs can be oxidatively metabolized to form hydroxylated polybrominated diphenyl ethers (OH-BDEs). While studies have examined behavioral deficits or alterations induced by exposure to PBDEs in both rodents and fish, no study to date has explored behavioral effects from exposure to OH-BDEs, which have been shown to have greater endocrine disrupting potential compared to PBDEs. In the present study, zebrafish (Danio rerio) were exposed during embryonic and larval development (0-6days post fertilization, dpf) to a PBDE metabolite, 6-hydroxy, 2,2',4,4' tetrabromodiphenyl ether (10-50nM) and then examined for short and long-term behavioral effects. Exposed zebrafish tested as larvae (6dpf) showed an altered swimming response to light-dark transitions, exhibiting hypoactivity in light periods compared to control fish. When fish expo...
Brain research bulletin, 2015
Nicotine and chlorpyrifos are developmental neurotoxicants that target serotonin systems. We exam... more Nicotine and chlorpyrifos are developmental neurotoxicants that target serotonin systems. We examined whether prenatal nicotine exposure alters the subsequent response to chlorpyrifos given postnatally. Pregnant rats received nicotine throughout gestation at 3mg/kg/day, a regimen designed to achieve plasma levels seen in smokers; chlorpyrifos was given to pups on postnatal days (PN) 1-4 at 1mg/kg, just above the detection threshold for brain cholinesterase inhibition. We assessed long-term effects from adolescence (PN30) through full adulthood (PN150), measuring the expression of serotonin receptors and serotonin turnover (index of presynaptic impulse activity) in cerebrocortical brain regions encompassing the projections that are known targets for nicotine and chlorpyrifos. Nicotine or chlorpyrifos individually increased the expression of serotonin receptors, with greater effects on males than on females and with distinct temporal and regional patterns indicative of adaptive synapt...
Pharmacology Biochemistry and Behavior, 2015
Over the last decade, zebrafish (Danio rerio) have become valuable as a complementary model in be... more Over the last decade, zebrafish (Danio rerio) have become valuable as a complementary model in behavioral pharmacology, opening a new avenue for understanding the relationships between drug action and behavior. This species offers a useful intermediate approach bridging the gap between in vitro studies and traditional mammalian models. Zebrafish offer great advantages of economy compared to their rodent counterparts, their complex brains and behavioral repertoire offer great translational potential relative to in vitro models. The development and validation of a variety of tests to measure behavior, including cognition, in zebrafish has set the stage for the use of this animal for behavioral pharmacology studies. This has led to research into the basic mechanisms of cognitive function as well as screening for potential cognition-improving drug therapies, among other lines of research. As with all models, zebrafish have limitations, which spans pharmacokinetic challenges to difficulties quantifying behavior. The use, efficacy and limitations associated with a zebrafish model of cognitive function are discussed in this review, within the context of behavioral pharmacology.
A zebrafish model of the persisting neurobehavioral impairment caused by developmental chlorpyrifos exposure
Neurotoxicology and Teratology, 2009
Neurotoxicology and teratology, Jan 16, 2015
Developmental exposure to ethanol has long been known to cause persisting neurobehavioral impairm... more Developmental exposure to ethanol has long been known to cause persisting neurobehavioral impairment. However, the neural and behavioral mechanisms underlying these deficits and the importance of exposure timing are not well-characterized. Given the importance of timing and sequence in neurodevelopment it would be expected that alcohol intoxication at different developmental periods would result in distinct neurobehavioral consequences. Zebrafish embryos were exposed to ethanol (0%, 1%, 3%) at either 8-10 or 24-27h post-fertilization (hpf) then reared to adolescence and evaluated on several behavioral endpoints. Habituation to a repeated environmental stimulus and overall sensorimotor function were assessed using a tap startle test; measurements of anxiety and exploration behavior were made following introduction to a novel tank; and spatial discrimination learning was assessed using aversive control in a three-chambered apparatus. Overt signs of dysmorphogenesis were also scored (i...
Toxicological sciences : an official journal of the Society of Toxicology, 2014
Organophosphate flame retardants (OPFRs) are common replacements for the phased-out polybrominate... more Organophosphate flame retardants (OPFRs) are common replacements for the phased-out polybrominated diphenyl ethers (PBDEs) and have been detected at high concentrations in environmental samples. OPFRs are structurally similar to organophosphate pesticides and may adversely affect the developing nervous system. This study evaluated the overt toxicity, uptake, and neurobehavioral effects of tris (1,3-dichloro-2-propyl) phosphate (TDCPP), tris (2-chloroethyl) phosphate (TCEP), tris (1-chloro-2-propyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP) in early life stage zebrafish. Chlorpyrifos was used as a positive control. For overt toxicity and neurobehavioral assessments, zebrafish were exposed from 0 to 5 days postfertilization (dpf). Hatching, death, or malformations were evaluated daily. Teratogenic effects were scored by visual examination on 6 dpf. To evaluate uptake and metabolism, zebrafish were exposed to 1 µM of each organophosphate (OP) flame retardant and ...
revneuro, 2011
Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxioly... more Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in zebrafish makes them outstanding models for helping to determine the neuromolecular mechanisms for psychoactive drugs. However, to use zebrafish as a translational model we must have validated, sensitive and efficient behavioral tests. In a series of studies, our lab has developed tests of cognitive function and stress response, which are sensitive to drug effects in a similar manner as rodent models and humans for cognitive enhancement and alleviating stress response. In particular, the three-cha...
Psychopharmacology, 2006
Rationale This review provides insight for the judicious selection of nicotine dose ranges and ro... more Rationale This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species
Neurotoxicology and Teratology, 2011
Zebrafish are increasingly used for developmental neurotoxicity testing because early embryonic e... more Zebrafish are increasingly used for developmental neurotoxicity testing because early embryonic events are easy to visualize, exposures are done without affecting the mother and the rapid development of zebrafish allows for high throughput testing. We used zebrafish to examine how exposures to three different organophosphorus pesticides (chlorpyrifos, diazinon and parathion) over the first five days of embryonic and larval development of zebrafish affected their survival, acetylcholinesterase (AChE) activity and behavior. We show that at non-lethal, equimolar concentrations, chlorpyrifos (CPF) is more effective at equimolar concentrations than diazinon (DZN) and parathion (PA) in producing AChE inhibition. As concentrations of DZN and PA are raised, lethality occurs before they can produce the degree of AChE inhibition observed with CPF at 300nM. Because of its availability outside the mother at the time of fertilization, zebrafish provides a complementary model for studying the neurotoxicity of very early developmental exposures.
Neurotoxicology and Teratology, 2011
As more adults take the stimulant medication methylphenidate to treat attention deficit hyperacti... more As more adults take the stimulant medication methylphenidate to treat attention deficit hyperactivity disorder (ADHD) residual type, the risk arises with regard to the potential risks of early developmental exposure if people taking the medication become pregnant. We studied the neurobehavioral effects of methylphenidate in zebrafish. Zebrafish offer cellular reporter systems, continuous visual access and molecular interventions such as morpholinos to help determine critical mechanisms underlying neurobehavioral teratogenicity. Previously, we had seen that persisting neurobehavioral impairment in zebrafish with developmental chlorpyrifos exposure was associated with disturbed dopamine systems. Because methylphenidate is an indirect dopamine agonist, it was thought that it might also cause persistent behavioral impairment after developmental exposure. Zebrafish embryos were exposed to the ADHD stimulant medication methylphenidate 0-5 days post fertilization (12.5-50 mg/l). They were tested for long-term behavioral effects as adults. Methylphenidate exposure (50 mg/l) caused significant increases in dopamine, norepinepherine and serotonin on day 6 but not day 30 after fertilization. In the novel tank diving test of predatory avoidance developmental methylphenidate (50 mg/l) caused a significant reduction in the normal diving response. In the three-chamber spatial learning task early developmental methylphenidate (50 mg/l) caused a significant impairment in choice accuracy. These data show that early developmental exposure of zebrafish to methylphenidate causes a long-term impairment in neurobehavioral plasticity. The identification of these functional deficits in zebrafish enables further studies with this model to determine how molecular and cellular mechanisms are disturbed to arrive at this compromised state.
Neurotoxicology and Teratology, 2011
Developmental exposure of rats to the pesticide chlorpyrifos (CPF) causes persistent neurobehavio... more Developmental exposure of rats to the pesticide chlorpyrifos (CPF) causes persistent neurobehavioral impairment. In a parallel series of studies with zebrafish, we have also found persisting behavioral dysfunction after developmental CPF exposure. We have developed a battery of measures of zebrafish behavior, which are reliable and sensitive to toxicant-induced damage. This study determined the critical duration of developmental CPF exposure for causing persisting neurobehavioral effects. Tests of sensorimotor response (tap startle response and habituation), stress response (novel tank diving test) and learning (3-chamber tank spatial discrimination) were conducted with adult zebrafish after early developmental CPF exposure. The CPF exposure level was 100 ng/ml with durations of 0-1, 0-2, 0-3, 0-4 and 0-5 days after fertilization. Developmental CPF exposure had persisting behavioral effects in zebrafish tested as adults. In the tactile startle test, CPF exposed fish showed decreased habituation to startle and a trend toward increased overall startle response. In the novel tank exploration test, exposed fish showed decreased escape diving response and increased swimming activity. In the 3-chamber learning test, the 0-5 day CPF exposure group had a significantly lower learning rate. There was evidence for persisting declines in brain dopamine and norepinepherine levels after developmental CPF exposure. In all of the measures the clearest persistent effects were seen in fish exposed for the full duration of five days after fertilization. In a follow-up experiment there were some indications for persisting behavioral effects after exposure during only the later phase of this developmental window. This study demonstrated the selective long-term neurobehavioral alterations caused by exposure to CPF in zebrafish. The zebrafish model can facilitate the determination of the molecular mechanisms underlying long-term neurobehavioral impairment after developmental toxicant exposure.
Erratum to “Chlorpyrifos exposure of developing zebrafish: effects on survival and long-term effects on response latency and spatial discrimination” [Neurotoxicol. Teratol. 25 (2003) 51–57]
Neurotoxicology and Teratology, 2003
Neurotoxicology and Teratology, 2010
Neurotoxicology and Teratology, 2010
Neurotoxicology and Teratology, 2008
Background-Developmental neurotoxicity of organophosphorous insecticides (OPs) involves multiple ... more Background-Developmental neurotoxicity of organophosphorous insecticides (OPs) involves multiple mechanisms in addition to cholinesterase inhibition. We have found persisting effects of developmental chlorpyrifos (CPF) and diazinon (DZN) on cholinergic and serotonergic neurotransmitter systems and gene expression as well as behavioral function. Both molecular/ neurochemical and behavioral effects of developmental OP exposure have been seen at doses below those which cause appreciable cholinesterase inhibition. Objectives-We sought to determine if developmental DZN exposure at doses which do not produce significant acetylcholinesterase inhibition cause cognitive deficits. Methods-Rats were exposed to DZN on postnatal days 1-4 at doses (0.5 and 2 mg/kg/d) that span the threshold for cholinesterase inhibition. They were later examined with a cognitive battery tests similar to that used with CPF. Results-In the T-maze DZN caused significant hyperactivity in the initial trials of the session, but not later. In a longer assessment of locomotor activity no DZN-induced changes were seen over a 1hour session. Prepulse inhibition was reduced by DZN exposure selectively in males vs. females; DZN eliminated the sex difference present in controls. In the radial maze, the lower but not higher DZN dose significantly impaired spatial learning. This has previously been seen with CPF as well. The lower dose DZN group also showed significantly greater sensitivity to the memory-impairing effects of the anticholinergic drug scopolamine. Conclusions-Neonatal DZN exposure below the threshold for appreciable cholinesterase inhibition caused neurocognitive deficits in adulthood. The addition of some inhibition of AChE with a higher dose reversed the cognitive impairment. This non-monotonic dose-effect function has also been seen with neurochemical effects. Some of the DZN effects on cognition resemble those seen earlier for CPF, some differ. Our data suggest that DZN and CPF affect transmitter systems
Neurotoxicology and Teratology, 2011
Neurotoxicology and Teratology, 2011
control and MeOH males (24.5 g-31.2 g). There were no significant differences in sperm concentrat... more control and MeOH males (24.5 g-31.2 g). There were no significant differences in sperm concentration (1100-1669 × 10 6 /ml), motility (81.3%-87.9%) or normal morphology (84.0%-96.3%) between groups. However, there was a significant linear trend for increased sperm mediated oocyte activation (63.8%-85.0%) with increasing MeOH exposure (χ 2 = 5.60, p = 0.02). There was no significant difference in ovarian or uterine weight between groups (0.25 g-0.39 g and 3.75-6.08 g, respectively). There was a significant linear trend for a decrease in IVM rate with increasing MeOH exposure (χ 2 = 7.53, p = 0.006) attributed to Metaphase I arrest. IVM rates were significantly lower in the 1800 ppm group compared with the control (39.5% v. 27.8%). While there was no effect of MeOH exposure on serum AMH (5.79-13.57 ng/ml) a positive correlation existed between serum AMH and the total number of oocytes retrieved and the total number of mature oocytes post-IVM (r = 0.15-0.19, t = 3.26-5.15, n = 19, p < 0.05). While these findings suggest that there is no overt effect on gonadal morphology, gamete function may be adversely affected in females following FME.
Neurotoxicology and Teratology, 2011
NeuroToxicology, 2017
Background-Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants until the ... more Background-Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants until the early 2000s, mainly in home furnishings and electronics. The persistence of PBDEs in the environment leads to continued ubiquitous exposure to low levels, with infants and children experiencing higher exposures than adults. Accumulating evidence suggest that low-level exposures during early life stages can affect brain development and lead to long-term behavioral impairments. We investigated the effects of zebrafish exposure to low doses of the two prominent PBDEs; 2,2',4,4',5,-Pentabromodiphenyl ether (BDE-99) and 2,2',4,4',-Tetrabromodiphenyl ether (BDE-47), during embryo-development on short-and long-term behavioral endpoints. We included the organophosphate pesticide chlorpyrifos (CPF) due to its well documented neurotoxicity across species from zebrafish to humans. Methods-Zebrafish embryos were exposed to the following individual treatments; 0.1% DMSO (vehicle control); 0.3 µM CPF; 0.01, 0.03, 0.1, 0.3 µM BDE-47; 0.003, 0.03, 0.3, 1, 3, 10, 20 µM BDE-99 from 5 until 120 hours post fertilization (hpf). Low exposure levels were determined as those not causing immediate overt toxicity, and behavior assays were conducted in the low-level range. At 144 hpf the larvae were tested for locomotor activity. At approximately 6 months of age adult zebrafish were tested in a behavioral battery including assays for anxiety-related behavior, sensorimotor response and habituation, social interaction, and predator avoidance. Results-In the short-term, larval locomotor activity was reduced in larvae treated with 0.3 µM CPF and 0.1 µM BDE-47. BDE-99 treatment caused non-monotonic dose effects, with 0.3 µM *
Neurotoxicology and Teratology, 2015
BACKGROUND-FireMaster® 550 (FM 550) is the second most commonly used flame retardant (FR) product... more BACKGROUND-FireMaster® 550 (FM 550) is the second most commonly used flame retardant (FR) product in consumer goods and has been detected in household dust samples. However, neurobehavioral effects associated with exposure have not been characterized in detail. We investigated the behavioral effects of FM 550 in zebrafish to facilitate the integration of the cellular and molecular effects of FM 550 with its behavioral consequences. The effects of developmental FM 550 exposure on zebrafish larvae swimming shortly after the end of exposure as well as the persisting effects of this exposure on adolescent behavior were studied. In addition, the acute effects of FM 550 on behavior with exposure during adolescence in zebrafish were studied. METHODS-Developmental exposure to 0, 0.01, 0.1 or 1 mg/L of FM 550 via immersion spanned 0-5 days post fertilization, with larval testing on day 6 and adolescent testing on days 40-45. Acute adolescent (45 dpf) exposure was to 0, 1.0 or 3.0 mg/L of FM 550 via immersion, for 24 hrs, with testing 2 hr or 1 week later. The vehicle condition was colony tank water with .0004% (developmental) or .0012% (adolescent) DMSO. Zebrafish behavior was characterized across several domains including learning, social affiliation, sensorimotor function, predator escape, and novel environment exploration. RESULTS-Persisting effects of developmental FM 550 exposure included a significant (p < 0.01) reduction in social behavior among all dose groups. Acute FM550 exposure during adolescence caused hypoactivity and reduced social behavior (p's < 0.05) when the fish were tested 2 hr after exposure. These effects were attenuated at the 1 week post exposure testing point. DISCUSSION-Taken together, these data indicate that FM 550 may cause persisting neurobehavioral alterations to social behavior in the absence of perturbations along other
Neurotoxicology and teratology, Jan 13, 2015
Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants that are widely detected... more Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants that are widely detected in the environment, biota, and humans. In mammals, PBDEs can be oxidatively metabolized to form hydroxylated polybrominated diphenyl ethers (OH-BDEs). While studies have examined behavioral deficits or alterations induced by exposure to PBDEs in both rodents and fish, no study to date has explored behavioral effects from exposure to OH-BDEs, which have been shown to have greater endocrine disrupting potential compared to PBDEs. In the present study, zebrafish (Danio rerio) were exposed during embryonic and larval development (0-6days post fertilization, dpf) to a PBDE metabolite, 6-hydroxy, 2,2',4,4' tetrabromodiphenyl ether (10-50nM) and then examined for short and long-term behavioral effects. Exposed zebrafish tested as larvae (6dpf) showed an altered swimming response to light-dark transitions, exhibiting hypoactivity in light periods compared to control fish. When fish expo...
Brain research bulletin, 2015
Nicotine and chlorpyrifos are developmental neurotoxicants that target serotonin systems. We exam... more Nicotine and chlorpyrifos are developmental neurotoxicants that target serotonin systems. We examined whether prenatal nicotine exposure alters the subsequent response to chlorpyrifos given postnatally. Pregnant rats received nicotine throughout gestation at 3mg/kg/day, a regimen designed to achieve plasma levels seen in smokers; chlorpyrifos was given to pups on postnatal days (PN) 1-4 at 1mg/kg, just above the detection threshold for brain cholinesterase inhibition. We assessed long-term effects from adolescence (PN30) through full adulthood (PN150), measuring the expression of serotonin receptors and serotonin turnover (index of presynaptic impulse activity) in cerebrocortical brain regions encompassing the projections that are known targets for nicotine and chlorpyrifos. Nicotine or chlorpyrifos individually increased the expression of serotonin receptors, with greater effects on males than on females and with distinct temporal and regional patterns indicative of adaptive synapt...
Pharmacology Biochemistry and Behavior, 2015
Over the last decade, zebrafish (Danio rerio) have become valuable as a complementary model in be... more Over the last decade, zebrafish (Danio rerio) have become valuable as a complementary model in behavioral pharmacology, opening a new avenue for understanding the relationships between drug action and behavior. This species offers a useful intermediate approach bridging the gap between in vitro studies and traditional mammalian models. Zebrafish offer great advantages of economy compared to their rodent counterparts, their complex brains and behavioral repertoire offer great translational potential relative to in vitro models. The development and validation of a variety of tests to measure behavior, including cognition, in zebrafish has set the stage for the use of this animal for behavioral pharmacology studies. This has led to research into the basic mechanisms of cognitive function as well as screening for potential cognition-improving drug therapies, among other lines of research. As with all models, zebrafish have limitations, which spans pharmacokinetic challenges to difficulties quantifying behavior. The use, efficacy and limitations associated with a zebrafish model of cognitive function are discussed in this review, within the context of behavioral pharmacology.
A zebrafish model of the persisting neurobehavioral impairment caused by developmental chlorpyrifos exposure
Neurotoxicology and Teratology, 2009
Neurotoxicology and teratology, Jan 16, 2015
Developmental exposure to ethanol has long been known to cause persisting neurobehavioral impairm... more Developmental exposure to ethanol has long been known to cause persisting neurobehavioral impairment. However, the neural and behavioral mechanisms underlying these deficits and the importance of exposure timing are not well-characterized. Given the importance of timing and sequence in neurodevelopment it would be expected that alcohol intoxication at different developmental periods would result in distinct neurobehavioral consequences. Zebrafish embryos were exposed to ethanol (0%, 1%, 3%) at either 8-10 or 24-27h post-fertilization (hpf) then reared to adolescence and evaluated on several behavioral endpoints. Habituation to a repeated environmental stimulus and overall sensorimotor function were assessed using a tap startle test; measurements of anxiety and exploration behavior were made following introduction to a novel tank; and spatial discrimination learning was assessed using aversive control in a three-chambered apparatus. Overt signs of dysmorphogenesis were also scored (i...
Toxicological sciences : an official journal of the Society of Toxicology, 2014
Organophosphate flame retardants (OPFRs) are common replacements for the phased-out polybrominate... more Organophosphate flame retardants (OPFRs) are common replacements for the phased-out polybrominated diphenyl ethers (PBDEs) and have been detected at high concentrations in environmental samples. OPFRs are structurally similar to organophosphate pesticides and may adversely affect the developing nervous system. This study evaluated the overt toxicity, uptake, and neurobehavioral effects of tris (1,3-dichloro-2-propyl) phosphate (TDCPP), tris (2-chloroethyl) phosphate (TCEP), tris (1-chloro-2-propyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP) in early life stage zebrafish. Chlorpyrifos was used as a positive control. For overt toxicity and neurobehavioral assessments, zebrafish were exposed from 0 to 5 days postfertilization (dpf). Hatching, death, or malformations were evaluated daily. Teratogenic effects were scored by visual examination on 6 dpf. To evaluate uptake and metabolism, zebrafish were exposed to 1 µM of each organophosphate (OP) flame retardant and ...
revneuro, 2011
Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxioly... more Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in zebrafish makes them outstanding models for helping to determine the neuromolecular mechanisms for psychoactive drugs. However, to use zebrafish as a translational model we must have validated, sensitive and efficient behavioral tests. In a series of studies, our lab has developed tests of cognitive function and stress response, which are sensitive to drug effects in a similar manner as rodent models and humans for cognitive enhancement and alleviating stress response. In particular, the three-cha...
Psychopharmacology, 2006
Rationale This review provides insight for the judicious selection of nicotine dose ranges and ro... more Rationale This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species
Neurotoxicology and Teratology, 2011
Zebrafish are increasingly used for developmental neurotoxicity testing because early embryonic e... more Zebrafish are increasingly used for developmental neurotoxicity testing because early embryonic events are easy to visualize, exposures are done without affecting the mother and the rapid development of zebrafish allows for high throughput testing. We used zebrafish to examine how exposures to three different organophosphorus pesticides (chlorpyrifos, diazinon and parathion) over the first five days of embryonic and larval development of zebrafish affected their survival, acetylcholinesterase (AChE) activity and behavior. We show that at non-lethal, equimolar concentrations, chlorpyrifos (CPF) is more effective at equimolar concentrations than diazinon (DZN) and parathion (PA) in producing AChE inhibition. As concentrations of DZN and PA are raised, lethality occurs before they can produce the degree of AChE inhibition observed with CPF at 300nM. Because of its availability outside the mother at the time of fertilization, zebrafish provides a complementary model for studying the neurotoxicity of very early developmental exposures.
Neurotoxicology and Teratology, 2011
As more adults take the stimulant medication methylphenidate to treat attention deficit hyperacti... more As more adults take the stimulant medication methylphenidate to treat attention deficit hyperactivity disorder (ADHD) residual type, the risk arises with regard to the potential risks of early developmental exposure if people taking the medication become pregnant. We studied the neurobehavioral effects of methylphenidate in zebrafish. Zebrafish offer cellular reporter systems, continuous visual access and molecular interventions such as morpholinos to help determine critical mechanisms underlying neurobehavioral teratogenicity. Previously, we had seen that persisting neurobehavioral impairment in zebrafish with developmental chlorpyrifos exposure was associated with disturbed dopamine systems. Because methylphenidate is an indirect dopamine agonist, it was thought that it might also cause persistent behavioral impairment after developmental exposure. Zebrafish embryos were exposed to the ADHD stimulant medication methylphenidate 0-5 days post fertilization (12.5-50 mg/l). They were tested for long-term behavioral effects as adults. Methylphenidate exposure (50 mg/l) caused significant increases in dopamine, norepinepherine and serotonin on day 6 but not day 30 after fertilization. In the novel tank diving test of predatory avoidance developmental methylphenidate (50 mg/l) caused a significant reduction in the normal diving response. In the three-chamber spatial learning task early developmental methylphenidate (50 mg/l) caused a significant impairment in choice accuracy. These data show that early developmental exposure of zebrafish to methylphenidate causes a long-term impairment in neurobehavioral plasticity. The identification of these functional deficits in zebrafish enables further studies with this model to determine how molecular and cellular mechanisms are disturbed to arrive at this compromised state.
Neurotoxicology and Teratology, 2011
Developmental exposure of rats to the pesticide chlorpyrifos (CPF) causes persistent neurobehavio... more Developmental exposure of rats to the pesticide chlorpyrifos (CPF) causes persistent neurobehavioral impairment. In a parallel series of studies with zebrafish, we have also found persisting behavioral dysfunction after developmental CPF exposure. We have developed a battery of measures of zebrafish behavior, which are reliable and sensitive to toxicant-induced damage. This study determined the critical duration of developmental CPF exposure for causing persisting neurobehavioral effects. Tests of sensorimotor response (tap startle response and habituation), stress response (novel tank diving test) and learning (3-chamber tank spatial discrimination) were conducted with adult zebrafish after early developmental CPF exposure. The CPF exposure level was 100 ng/ml with durations of 0-1, 0-2, 0-3, 0-4 and 0-5 days after fertilization. Developmental CPF exposure had persisting behavioral effects in zebrafish tested as adults. In the tactile startle test, CPF exposed fish showed decreased habituation to startle and a trend toward increased overall startle response. In the novel tank exploration test, exposed fish showed decreased escape diving response and increased swimming activity. In the 3-chamber learning test, the 0-5 day CPF exposure group had a significantly lower learning rate. There was evidence for persisting declines in brain dopamine and norepinepherine levels after developmental CPF exposure. In all of the measures the clearest persistent effects were seen in fish exposed for the full duration of five days after fertilization. In a follow-up experiment there were some indications for persisting behavioral effects after exposure during only the later phase of this developmental window. This study demonstrated the selective long-term neurobehavioral alterations caused by exposure to CPF in zebrafish. The zebrafish model can facilitate the determination of the molecular mechanisms underlying long-term neurobehavioral impairment after developmental toxicant exposure.
Erratum to “Chlorpyrifos exposure of developing zebrafish: effects on survival and long-term effects on response latency and spatial discrimination” [Neurotoxicol. Teratol. 25 (2003) 51–57]
Neurotoxicology and Teratology, 2003
Neurotoxicology and Teratology, 2010
Neurotoxicology and Teratology, 2010
Neurotoxicology and Teratology, 2008
Background-Developmental neurotoxicity of organophosphorous insecticides (OPs) involves multiple ... more Background-Developmental neurotoxicity of organophosphorous insecticides (OPs) involves multiple mechanisms in addition to cholinesterase inhibition. We have found persisting effects of developmental chlorpyrifos (CPF) and diazinon (DZN) on cholinergic and serotonergic neurotransmitter systems and gene expression as well as behavioral function. Both molecular/ neurochemical and behavioral effects of developmental OP exposure have been seen at doses below those which cause appreciable cholinesterase inhibition. Objectives-We sought to determine if developmental DZN exposure at doses which do not produce significant acetylcholinesterase inhibition cause cognitive deficits. Methods-Rats were exposed to DZN on postnatal days 1-4 at doses (0.5 and 2 mg/kg/d) that span the threshold for cholinesterase inhibition. They were later examined with a cognitive battery tests similar to that used with CPF. Results-In the T-maze DZN caused significant hyperactivity in the initial trials of the session, but not later. In a longer assessment of locomotor activity no DZN-induced changes were seen over a 1hour session. Prepulse inhibition was reduced by DZN exposure selectively in males vs. females; DZN eliminated the sex difference present in controls. In the radial maze, the lower but not higher DZN dose significantly impaired spatial learning. This has previously been seen with CPF as well. The lower dose DZN group also showed significantly greater sensitivity to the memory-impairing effects of the anticholinergic drug scopolamine. Conclusions-Neonatal DZN exposure below the threshold for appreciable cholinesterase inhibition caused neurocognitive deficits in adulthood. The addition of some inhibition of AChE with a higher dose reversed the cognitive impairment. This non-monotonic dose-effect function has also been seen with neurochemical effects. Some of the DZN effects on cognition resemble those seen earlier for CPF, some differ. Our data suggest that DZN and CPF affect transmitter systems