Kathy McDaniel - Academia.edu (original) (raw)

Papers by Kathy McDaniel

PubMed, 1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the... more The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. The effects of seven chemicals (acrylamide, bis-acrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin) were studied during two dosing regimens: single-dose and four-week repeated dosing. All participating laboratories generally could detect and characterize the effects of known neurotoxicants, even though there were some differences in outcome on specific endpoints. The results were further evaluated to assess the agreement across laboratories in the dose-response data at the expected times of maximal effect (time of peak effect for the single-dose studies, and during or at the end of dosing for repeated-exposure studies). Percent agreement was calculated as the percentage of laboratories agreeing on an outcome (whether it be a significant dose effect or not). As an alternative approach, slopes of the dose-response functions were calculated, and reliability of those slope estimates across laboratories and chemicals was determined. Reliability was defined as the degree of agreement across laboratories (intraclass correlation coefficient) of the dose-response slopes within and between chemicals. These reliability estimates were calculated for each domain and for each endpoint. Relative reliability of the endpoints was evaluated, and hypotheses concerning the influence of outlying data were tested. The data clearly showed that reliability was not influenced by the objectivity or subjectivity of the test measure. Thus these data provide additional information regarding the reliability and robustness of the tests across the participating laboratories.

Neurotoxicology and Teratology, Nov 1, 2007

Organotins such as monomethyltin (MMT) are widely used as heat stabilizers in PVC and CPVC piping... more Organotins such as monomethyltin (MMT) are widely used as heat stabilizers in PVC and CPVC piping, which results in their presence in drinking water supplies. Concern for neurotoxicity produced by organotin exposure during development has been raised by published findings of a deficit on a runway learning task in rat pups perinatally exposed to MMT (Noland EA, Taylor DH, Bull RJ. Monomethyl and trimethyltin compounds induce learning deficiencies in young rats. Neurobehav Toxicol Teratol 1982;4:539-44). The objective of these studies was to replicate the earlier publication and further define the dose-response characteristics of MMT following perinatal exposure. In Experiment 1, female Sprague-Dawley rats were exposed via drinking water to MMT (0, 10, 50, 245 ppm) before mating and throughout gestation and lactation (until weaning at postnatal day [PND] 21). Behavioral assessments of the offspring included: a runway test (PND 11) in which the rat pups learned to negotiate a runway for dry suckling reward; motor activity habituation (PNDs 13, 17, and 21); learning in the Morris water maze (as adults). Other endpoints in the offspring included measures of apoptosis (DNA fragmentation) at PND 22 and as adults, as well as brain weights and neuropathological evaluation at PND 2, 12, 22, and as adults. There were no effects on any measure of growth, development, cognitive function, or apoptosis following MMT exposure. There was a trend towards decreased brain weight in the high dose group. In addition, there was vacuolation of the neuropil in a focal area of the cerebral cortex of the adult offspring in all MMT dose groups (1-3 rats per treatment group). In Experiment 2, pregnant rats were exposed from gestational day 6 until weaning to 500 ppm MMT in drinking water. The offspring behavioral assessments again included the runway task (PND 11), motor activity habituation (PND 17), and Morris water maze (as adults). In this second study, MMT-exposed females consumed significantly less water than the controls throughout both gestation and lactation, although neither dam nor pup weights were affected. As in Experiment 1, MMT-exposure did not alter pup runway performance, motor activity, or cognitive function. These results indicate that perinatal exposure to MMT, even at concentrations which decrease fluid intake, does not result in significant neurobehavioral or cognitive deficits. While mild neuropathological lesions were observed in the adult offspring, the biological significance of this restricted finding is unclear.

The FASEB Journal, Apr 1, 2017

Studies in both humans and animals have shown that prenatal stress (PNS) can alter cognitive func... more Studies in both humans and animals have shown that prenatal stress (PNS) can alter cognitive function and other neurological behaviors in adult offspring. One possible underlying mechanism for this...

Journal of the Endocrine Society, 2019

Abstract Ozone exposure during implantation receptivity reduces fetal growth during gestation. In... more Abstract Ozone exposure during implantation receptivity reduces fetal growth during gestation. Intrauterine growth restriction is associated with increased metabolic disease risk as offspring age into adulthood. Therefore, the purpose of this study was to investigate the risk of obesity in offspring from ozone-exposed dams. Long-Evans dams were exposed to filtered air or 0.8 ppm ozone for 4-hours on gestation days 5 and 6. To assess metabolic risk, subsets of peri-adolescent offspring were fed a 45% high-fat diet (HFD) for 3-days, which is an established model of acute leptin and insulin resistance in rats. Over the 3-day challenge, HFD-fed offspring from ozone-exposed dams consumed more calories and had reduced metabolic rate compared to their low-fat diet (LFD)-fed controls. Accordingly, HFD-fed males from ozone-exposed dams had a nearly 300% increase in fat accrual compared to controls, whereas females failed to exhibit this response. Analysis of hypothalamic gene expression found reductions in the appetite-regulating genes including insulin receptor (Insr) and cocaine and amphetamine regulated transcript (Cartpt) in male offspring from ozone-exposed dams fed HFD. Gene-specific DNA methylation was performed using MeDIP-qPCR. Neither prenatal ozone nor HFD affected methylation of Insr or Cartpt in males. However, prenatal ozone exposure increased DNA methylation of Insr in females, which occurred without a decrease in Insr transcript. Together, our data suggest that a relatively acute exposure to ozone in early pregnancy alters energy balance in the offspring, the mechanisms and consequences of which is likely to be sex specific. Abstract does not reflect US EPA policy.

Neurotoxicology and Teratology, 2022

The developmental effects of chemicals that co-occur in vulnerable populations with elevated psyc... more The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL) and cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both sexes. Few effects related to the treatments were found on DRL or MWM. During cued CRT, Mn (2 and 4 mg/mL) and stress reduced accuracy in males, while stress and Mn (2 mg/mL) increased anticipatory responding and slowed decision time in both sexes. Stress combined with Mn (2 mg/mL) improved cued accuracy and decision time, and Mn attenuated the effect of stress on anticipatory responding in both sexes. Stress slowed female movement time but when combined with Mn (4 mg/mL) the effect of stress was attenuated. During uncued CRT, except for decision time (which replicated effects observed with the cued task), no other effects of Mn or its combination with stress occurred. Females remained negatively affected by stress in most uncued CRT performance measures, while stressed improved male uncued accuracy. Taken together these data do not support increased cognitive impairment produced by Mn when combined with stress. However, the effects of perinatal stress alone, on these cognitive functions may hinder the detection of effects due to chemical exposures and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals.

Neurotoxicology and Teratology, 2008

Neurotoxicology and teratology

Increased use of ethanol blends in gasoline suggests a need to assess the potential public health... more Increased use of ethanol blends in gasoline suggests a need to assess the potential public health risks of exposure to these fuels. Ethanol consumed during pregnancy is a teratogen. However, little is known about the potential developmental neurotoxicity of ethanol delivered by inhalation, the most likely route of exposure from gasoline-ethanol fuel blends. We evaluated the potential cognitive consequences of ethanol inhalation by exposing pregnant Long Evans rats to clean air or ethanol vapor from gestational days 9-20, a critical period of neuronal development. Concentrations of inhaled ethanol (5000, 10,000, or 21,000 ppm for 6.5h/day) produced modeled peak blood ethanol concentrations (BECs) in exposed dams of 2.3, 6.8, and 192 mg/dL, respectively. In offspring, no dose-related impairments were observed on spatial learning or working memory in the Morris water maze or in operant delayed match-to-position tests. Two measures showed significant effects in female offspring at all e...

Journal of Toxicology and Environmental Health, Part A, Oct 18, 2013

Studies incorporating both toxicokinetic and dynamic factors provide insight into chemical sensit... more Studies incorporating both toxicokinetic and dynamic factors provide insight into chemical sensitivity differences across the life span. Tissue (brain, plasma, liver) levels of the N-methyl carbamate carbaryl, and its metabolite 1-naphthol, were determined and related to brain and RBC cholinesterase (ChE) inhibition in the same animals. Dose-response (3, 7.5, 15, or 22.5 mg/kg, 40-45 min postdosing) and time course (3 or 15 mg/kg at 30, 60, 120, or 240 min postdosing) of acute effects of carbaryl (oral gavage) in preweanling (postnatal day [PND] 18) and adult male Brown Norway rats from adolescence to senescence (1, 4, 12, 24 mo) were compared. At all ages there were dose-related increases in carbaryl and 1-naphthol in the dose-response study, and the time-course study showed highest carbaryl levels at 30 min postdosing. There were, however, age-related differences in that the 1- and 4-mo rats showed the lowest levels of carbaryl and 1-naphthol, and PND18 and 24-mo rats had similar, higher levels. The fastest clearance (shortest half-lives) was observed in 1- and 4-mo rats. Carbaryl levels were generally higher than 1-naphthol in brain and plasma, but in liver, 1-naphthol levels were similar to or greater than carbaryl. Brain ChE inhibition closely tracked brain carbaryl concentrations regardless of the time after dosing, but there was more variability in the relationship between RBC ChE and plasma carbaryl levels. Within-subject analyses suggested somewhat more brain ChE inhibition at lower carbaryl levels only in the PND18 rats. These findings may reflect maturation followed by decline in kinetic factors over the life span.

Neurotoxicology and Teratology

Heptachlor is a persistent cyclodiene pesticide that affects GABAergic function. Recent reports i... more Heptachlor is a persistent cyclodiene pesticide that affects GABAergic function. Recent reports indicate that heptachlor exposure also alters dopamine transporter (DAT) expression and function in adult mice. The aim of this study was to determine whether gestational, perinatal, and/or adolescent heptachlor exposure in rats altered dopamine-receptor and DAT binding. Adolescent exposure to dieldrin was included to evaluate the generality of the findings. Sprague-Dawley rats received doses (po) ranging from 0 to 8.4 mg/kg/day of heptachlor, or dieldrin, 3 mg/kg/day, during different developmental periods. There were dose-related decreases in maternal weight gain and pup survival, as well as delayed righting reflex, at heptachlor doses>3 mg/kg/day. There were no changes in striatal dopamine receptor-D1 ( [ 3 H]SCH-23390) and-D2 ( [ 3 H]spiperone) binding in preweanling pups exposed perinatally to heptachlor, and no differences in the response

Neurotoxicology and Teratology

, the current study examined whether similar cognitive impairments would be seen in females. The ... more , the current study examined whether similar cognitive impairments would be seen in females. The study included a) females rather than males, b) an additional higher dose, and c) behavioral testing beginning at an earlier age and for a longer period of acquisition. Female Long Evans rats (n = 51; 12-14/group) were exposed to once-or twice-daily i. p. injections of either vehicle or 1.0 mg/kg nicotine on postnatal days 25-59 (P25-P59), but not thereafter. Beginning on P65, adult rats learned a 24-element serial pattern of responses, 123-234-345-456-567-678-781-818, for water reinforcement, where digits indicate clockwise positions of correct nosepoke receptacles in an 8-position circular array on successive trials. The sequence was composed of eight 3-element chunks, as in Fountain et al. (2008), but with the addition of an element ending the sequence that violated the otherwise simple pattern structure. For the first element of chunks, twice-daily injection nicotine rats showed impaired learning compared to once-daily injections. For the second two elements of each chunk, twice-daily injection nicotine rats showed a transient impairment in learning compared to once-daily injections and controls. At the last "violation element" of the pattern, both onceand twice-daily nicotine rats showed impaired learning, with twicedaily injection rats performing worse than once-daily injections rats. Taken together, these results demonstrate that adolescent nicotine exposure caused learning impairments and that it impaired different aspects of serial pattern learning differentially. Further, the results demonstrate a dose-dependent impairment for all aspects of the pattern, with rats receiving twice-daily injections (2 mg/kg/day) learning slower than those receiving once-daily injections (1 mg/kg/ day). The results add to evidence that adolescent nicotine exposure is a threat to adult cognitive capacity, demonstrating a new dosedependent effect and suggesting sex differences in comparison to prior work with male rats.

Neurotoxicology and Teratology

Neurotoxicology and Teratology

Human and animal studies indicate that maternal obesity can negatively impact aspects of metaboli... more Human and animal studies indicate that maternal obesity can negatively impact aspects of metabolism and neurodevelopment in the offspring. Not known, however, is whether maternal exercise can alter these adverse outcomes. In this study, Long-Evans female rats were provided a high fat (60%; HFD) or control diet (CD) 44days before mating and throughout gestation and lactation. Running wheels were available to half of each diet group during the gestational period only, resulting in four conditions: CD diet with (CDRW) or without (sedentary; CDSED) exercise, and HFD with (HFRW) or without (HFSED) exercise. Only male offspring (one per litter) were available for this study: they were put on control diet two weeks after weaning and examined using behavioral evaluations up to four months of age. Before weaning, offspring of CDRW dams weighed less than offspring from CDSED or HFD dams. After weaning, the lower weight in CDRW offspring generally persisted. Adult offspring from HFSED dams performed worse than the HFRW group in a Morris water maze during initial spatial training as well as reversal learning; memory was not impacted. No differences between groups were seen in tests of novel object recognition, social approach, or chocolate milk preference. Thus, maternal diet and exercise produced differential effects on body weights and cognitive behaviors in the offspring, and the data demonstrate a positive impact of maternal exercise on the offspring in that it ameliorated some deleterious behavioral effects of a maternal high fat diet.

Toxicology and applied pharmacology, Jan 15, 2016

Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavi... more Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metrics. Products of cyhalothrin, a type II pyrethroid, include mixtures of isomers (e.g., λ-cyhalothrin) as well as enriched active isomers (e.g., γ-cyhalothrin). We measured acute changes in locomotor activity in adult male rats and directly correlated these changes to peak brain and plasma concentrations of λ- and γ-cyhalothrin using a within-subject design. One-hour locomotor activity studies were conducted 1.5h after oral gavage dosing, and immediately thereafter plasma and brains were collected for analyzing tissue levels using LC/MS/MS methods. Both isomers produced dose-related decreases in activity counts, and the effective dose range for γ-cyhalothrin was lower than for λ-cyhalothrin. Doses calculated to d...

Toxicology and Applied Pharmacology, Apr 30, 1991

A functional observational battery (FOB) was utilized to assess the effects of 3-day exposure to ... more A functional observational battery (FOB) was utilized to assess the effects of 3-day exposure to the formamidine pesticide amitraz in outbred Sprague-Dawleyderived and inbred Fischer-344-derived (F344) rats (both from Charles River Laboratories) and in outbred Long-Evans rats obtained from two commercial suppliers (Charles River Breeding Laboratories and Blue Spruce Farms). Significant strain and stock differences were obtained in baseline values for one-third of the FOB measures. In most cases, F344 rats were different from the others. Characteristic signs of amitraz exposure consisting of increased excitability, hyperreactivity, and physiological and autonomic changes were evident in all treated rats. These effects increased with repeated dosing, and many were still present 6 days after dosing. On individual measures, there were differences between the strains and stocks in terms of sensitivity and time course of amitraz effects. In general, Blue Spruce Long-Evans rats displayed more effects of amitraz and F344 rats recovered more quickly than others. Although Sprague-Dawley rats showed the least effect overall, they displayed the largest increases in the sensorimotor responses to stimuli. These data indicate that although some behavioral and physiological parameters showed strain and supplier differences, in both baseline values and the effects of amitraz, conclusions concerning its neurotoxic potential in a screening context would be similar. 0 1991 Academic PESS, IIK. ' The research described in this article has been supported by the U.S. Environmental Protection Agency Contract (No. 68-02-4450) to NSI Technology Services, Inc. This manuscript has been reviewed by the Health Effects Research Laboratory, U.S. E.P.A., and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ' Portions of this study were presented at the 29th annual

Toxicology, Feb 12, 2007

The Safe Drinking Water Act requires that the U.S. EPA consider noncancer endpoints for the asses... more The Safe Drinking Water Act requires that the U.S. EPA consider noncancer endpoints for the assessment of adverse human health effects of disinfection by-products (DBPs). As an extension of our studies in which we demonstrated neurotoxicity at relatively low levels of dibromo-and dichloroacetic acids, we examined the potential neurotoxicity of other classes of DBPs. Bromodichloromethane (BDCM) and dibromoacetonitrile (DBAN) were administered to male and female F-344 rats via drinking water for 6 months. During exposure, rats were tested for neurobehavioral effects using a functional observational battery and motor activity, followed by perfusion fixation for neuropathological evaluation at the end of exposure. Calculating for chemical loss, fluid consumption, and body weight, average intakes were approximately: 9, 27, and 72 mg/(kg day) BDCM, and 5, 12, and 29 mg/(kg day) DBAN. Fluid consumption was decreased in most treatment groups, but body weight gain was altered only at the high concentrations. There were few neurobehavioral changes, and these were not considered toxicologically relevant. Of the general observations, there was only minimally decreased body tone in DBAN-treated high-dose males. Treatment-related neuropathological findings were not observed. Lowered fluid consumption was the most sensitive and consistent endpoint in the present studies. Thus, unlike the haloacetic acids, neurotoxicity may not be a concern for toxicity of halomethanes or haloacetonitriles.

PubMed, 1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the... more The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. The effects of seven chemicals (acrylamide, bis-acrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin) were studied during two dosing regimens: single-dose and four-week repeated dosing. All participating laboratories generally could detect and characterize the effects of known neurotoxicants, even though there were some differences in outcome on specific endpoints. The results were further evaluated to assess the agreement across laboratories in the dose-response data at the expected times of maximal effect (time of peak effect for the single-dose studies, and during or at the end of dosing for repeated-exposure studies). Percent agreement was calculated as the percentage of laboratories agreeing on an outcome (whether it be a significant dose effect or not). As an alternative approach, slopes of the dose-response functions were calculated, and reliability of those slope estimates across laboratories and chemicals was determined. Reliability was defined as the degree of agreement across laboratories (intraclass correlation coefficient) of the dose-response slopes within and between chemicals. These reliability estimates were calculated for each domain and for each endpoint. Relative reliability of the endpoints was evaluated, and hypotheses concerning the influence of outlying data were tested. The data clearly showed that reliability was not influenced by the objectivity or subjectivity of the test measure. Thus these data provide additional information regarding the reliability and robustness of the tests across the participating laboratories.

Neurotoxicology and Teratology, Nov 1, 2007

Organotins such as monomethyltin (MMT) are widely used as heat stabilizers in PVC and CPVC piping... more Organotins such as monomethyltin (MMT) are widely used as heat stabilizers in PVC and CPVC piping, which results in their presence in drinking water supplies. Concern for neurotoxicity produced by organotin exposure during development has been raised by published findings of a deficit on a runway learning task in rat pups perinatally exposed to MMT (Noland EA, Taylor DH, Bull RJ. Monomethyl and trimethyltin compounds induce learning deficiencies in young rats. Neurobehav Toxicol Teratol 1982;4:539-44). The objective of these studies was to replicate the earlier publication and further define the dose-response characteristics of MMT following perinatal exposure. In Experiment 1, female Sprague-Dawley rats were exposed via drinking water to MMT (0, 10, 50, 245 ppm) before mating and throughout gestation and lactation (until weaning at postnatal day [PND] 21). Behavioral assessments of the offspring included: a runway test (PND 11) in which the rat pups learned to negotiate a runway for dry suckling reward; motor activity habituation (PNDs 13, 17, and 21); learning in the Morris water maze (as adults). Other endpoints in the offspring included measures of apoptosis (DNA fragmentation) at PND 22 and as adults, as well as brain weights and neuropathological evaluation at PND 2, 12, 22, and as adults. There were no effects on any measure of growth, development, cognitive function, or apoptosis following MMT exposure. There was a trend towards decreased brain weight in the high dose group. In addition, there was vacuolation of the neuropil in a focal area of the cerebral cortex of the adult offspring in all MMT dose groups (1-3 rats per treatment group). In Experiment 2, pregnant rats were exposed from gestational day 6 until weaning to 500 ppm MMT in drinking water. The offspring behavioral assessments again included the runway task (PND 11), motor activity habituation (PND 17), and Morris water maze (as adults). In this second study, MMT-exposed females consumed significantly less water than the controls throughout both gestation and lactation, although neither dam nor pup weights were affected. As in Experiment 1, MMT-exposure did not alter pup runway performance, motor activity, or cognitive function. These results indicate that perinatal exposure to MMT, even at concentrations which decrease fluid intake, does not result in significant neurobehavioral or cognitive deficits. While mild neuropathological lesions were observed in the adult offspring, the biological significance of this restricted finding is unclear.

The FASEB Journal, Apr 1, 2017

Studies in both humans and animals have shown that prenatal stress (PNS) can alter cognitive func... more Studies in both humans and animals have shown that prenatal stress (PNS) can alter cognitive function and other neurological behaviors in adult offspring. One possible underlying mechanism for this...

Journal of the Endocrine Society, 2019

Abstract Ozone exposure during implantation receptivity reduces fetal growth during gestation. In... more Abstract Ozone exposure during implantation receptivity reduces fetal growth during gestation. Intrauterine growth restriction is associated with increased metabolic disease risk as offspring age into adulthood. Therefore, the purpose of this study was to investigate the risk of obesity in offspring from ozone-exposed dams. Long-Evans dams were exposed to filtered air or 0.8 ppm ozone for 4-hours on gestation days 5 and 6. To assess metabolic risk, subsets of peri-adolescent offspring were fed a 45% high-fat diet (HFD) for 3-days, which is an established model of acute leptin and insulin resistance in rats. Over the 3-day challenge, HFD-fed offspring from ozone-exposed dams consumed more calories and had reduced metabolic rate compared to their low-fat diet (LFD)-fed controls. Accordingly, HFD-fed males from ozone-exposed dams had a nearly 300% increase in fat accrual compared to controls, whereas females failed to exhibit this response. Analysis of hypothalamic gene expression found reductions in the appetite-regulating genes including insulin receptor (Insr) and cocaine and amphetamine regulated transcript (Cartpt) in male offspring from ozone-exposed dams fed HFD. Gene-specific DNA methylation was performed using MeDIP-qPCR. Neither prenatal ozone nor HFD affected methylation of Insr or Cartpt in males. However, prenatal ozone exposure increased DNA methylation of Insr in females, which occurred without a decrease in Insr transcript. Together, our data suggest that a relatively acute exposure to ozone in early pregnancy alters energy balance in the offspring, the mechanisms and consequences of which is likely to be sex specific. Abstract does not reflect US EPA policy.

Neurotoxicology and Teratology, 2022

The developmental effects of chemicals that co-occur in vulnerable populations with elevated psyc... more The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL) and cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both sexes. Few effects related to the treatments were found on DRL or MWM. During cued CRT, Mn (2 and 4 mg/mL) and stress reduced accuracy in males, while stress and Mn (2 mg/mL) increased anticipatory responding and slowed decision time in both sexes. Stress combined with Mn (2 mg/mL) improved cued accuracy and decision time, and Mn attenuated the effect of stress on anticipatory responding in both sexes. Stress slowed female movement time but when combined with Mn (4 mg/mL) the effect of stress was attenuated. During uncued CRT, except for decision time (which replicated effects observed with the cued task), no other effects of Mn or its combination with stress occurred. Females remained negatively affected by stress in most uncued CRT performance measures, while stressed improved male uncued accuracy. Taken together these data do not support increased cognitive impairment produced by Mn when combined with stress. However, the effects of perinatal stress alone, on these cognitive functions may hinder the detection of effects due to chemical exposures and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals.

Neurotoxicology and Teratology, 2008

Neurotoxicology and teratology

Increased use of ethanol blends in gasoline suggests a need to assess the potential public health... more Increased use of ethanol blends in gasoline suggests a need to assess the potential public health risks of exposure to these fuels. Ethanol consumed during pregnancy is a teratogen. However, little is known about the potential developmental neurotoxicity of ethanol delivered by inhalation, the most likely route of exposure from gasoline-ethanol fuel blends. We evaluated the potential cognitive consequences of ethanol inhalation by exposing pregnant Long Evans rats to clean air or ethanol vapor from gestational days 9-20, a critical period of neuronal development. Concentrations of inhaled ethanol (5000, 10,000, or 21,000 ppm for 6.5h/day) produced modeled peak blood ethanol concentrations (BECs) in exposed dams of 2.3, 6.8, and 192 mg/dL, respectively. In offspring, no dose-related impairments were observed on spatial learning or working memory in the Morris water maze or in operant delayed match-to-position tests. Two measures showed significant effects in female offspring at all e...

Journal of Toxicology and Environmental Health, Part A, Oct 18, 2013

Studies incorporating both toxicokinetic and dynamic factors provide insight into chemical sensit... more Studies incorporating both toxicokinetic and dynamic factors provide insight into chemical sensitivity differences across the life span. Tissue (brain, plasma, liver) levels of the N-methyl carbamate carbaryl, and its metabolite 1-naphthol, were determined and related to brain and RBC cholinesterase (ChE) inhibition in the same animals. Dose-response (3, 7.5, 15, or 22.5 mg/kg, 40-45 min postdosing) and time course (3 or 15 mg/kg at 30, 60, 120, or 240 min postdosing) of acute effects of carbaryl (oral gavage) in preweanling (postnatal day [PND] 18) and adult male Brown Norway rats from adolescence to senescence (1, 4, 12, 24 mo) were compared. At all ages there were dose-related increases in carbaryl and 1-naphthol in the dose-response study, and the time-course study showed highest carbaryl levels at 30 min postdosing. There were, however, age-related differences in that the 1- and 4-mo rats showed the lowest levels of carbaryl and 1-naphthol, and PND18 and 24-mo rats had similar, higher levels. The fastest clearance (shortest half-lives) was observed in 1- and 4-mo rats. Carbaryl levels were generally higher than 1-naphthol in brain and plasma, but in liver, 1-naphthol levels were similar to or greater than carbaryl. Brain ChE inhibition closely tracked brain carbaryl concentrations regardless of the time after dosing, but there was more variability in the relationship between RBC ChE and plasma carbaryl levels. Within-subject analyses suggested somewhat more brain ChE inhibition at lower carbaryl levels only in the PND18 rats. These findings may reflect maturation followed by decline in kinetic factors over the life span.

Neurotoxicology and Teratology

Heptachlor is a persistent cyclodiene pesticide that affects GABAergic function. Recent reports i... more Heptachlor is a persistent cyclodiene pesticide that affects GABAergic function. Recent reports indicate that heptachlor exposure also alters dopamine transporter (DAT) expression and function in adult mice. The aim of this study was to determine whether gestational, perinatal, and/or adolescent heptachlor exposure in rats altered dopamine-receptor and DAT binding. Adolescent exposure to dieldrin was included to evaluate the generality of the findings. Sprague-Dawley rats received doses (po) ranging from 0 to 8.4 mg/kg/day of heptachlor, or dieldrin, 3 mg/kg/day, during different developmental periods. There were dose-related decreases in maternal weight gain and pup survival, as well as delayed righting reflex, at heptachlor doses>3 mg/kg/day. There were no changes in striatal dopamine receptor-D1 ( [ 3 H]SCH-23390) and-D2 ( [ 3 H]spiperone) binding in preweanling pups exposed perinatally to heptachlor, and no differences in the response

Neurotoxicology and Teratology

, the current study examined whether similar cognitive impairments would be seen in females. The ... more , the current study examined whether similar cognitive impairments would be seen in females. The study included a) females rather than males, b) an additional higher dose, and c) behavioral testing beginning at an earlier age and for a longer period of acquisition. Female Long Evans rats (n = 51; 12-14/group) were exposed to once-or twice-daily i. p. injections of either vehicle or 1.0 mg/kg nicotine on postnatal days 25-59 (P25-P59), but not thereafter. Beginning on P65, adult rats learned a 24-element serial pattern of responses, 123-234-345-456-567-678-781-818, for water reinforcement, where digits indicate clockwise positions of correct nosepoke receptacles in an 8-position circular array on successive trials. The sequence was composed of eight 3-element chunks, as in Fountain et al. (2008), but with the addition of an element ending the sequence that violated the otherwise simple pattern structure. For the first element of chunks, twice-daily injection nicotine rats showed impaired learning compared to once-daily injections. For the second two elements of each chunk, twice-daily injection nicotine rats showed a transient impairment in learning compared to once-daily injections and controls. At the last "violation element" of the pattern, both onceand twice-daily nicotine rats showed impaired learning, with twicedaily injection rats performing worse than once-daily injections rats. Taken together, these results demonstrate that adolescent nicotine exposure caused learning impairments and that it impaired different aspects of serial pattern learning differentially. Further, the results demonstrate a dose-dependent impairment for all aspects of the pattern, with rats receiving twice-daily injections (2 mg/kg/day) learning slower than those receiving once-daily injections (1 mg/kg/ day). The results add to evidence that adolescent nicotine exposure is a threat to adult cognitive capacity, demonstrating a new dosedependent effect and suggesting sex differences in comparison to prior work with male rats.

Neurotoxicology and Teratology

Neurotoxicology and Teratology

Human and animal studies indicate that maternal obesity can negatively impact aspects of metaboli... more Human and animal studies indicate that maternal obesity can negatively impact aspects of metabolism and neurodevelopment in the offspring. Not known, however, is whether maternal exercise can alter these adverse outcomes. In this study, Long-Evans female rats were provided a high fat (60%; HFD) or control diet (CD) 44days before mating and throughout gestation and lactation. Running wheels were available to half of each diet group during the gestational period only, resulting in four conditions: CD diet with (CDRW) or without (sedentary; CDSED) exercise, and HFD with (HFRW) or without (HFSED) exercise. Only male offspring (one per litter) were available for this study: they were put on control diet two weeks after weaning and examined using behavioral evaluations up to four months of age. Before weaning, offspring of CDRW dams weighed less than offspring from CDSED or HFD dams. After weaning, the lower weight in CDRW offspring generally persisted. Adult offspring from HFSED dams performed worse than the HFRW group in a Morris water maze during initial spatial training as well as reversal learning; memory was not impacted. No differences between groups were seen in tests of novel object recognition, social approach, or chocolate milk preference. Thus, maternal diet and exercise produced differential effects on body weights and cognitive behaviors in the offspring, and the data demonstrate a positive impact of maternal exercise on the offspring in that it ameliorated some deleterious behavioral effects of a maternal high fat diet.

Toxicology and applied pharmacology, Jan 15, 2016

Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavi... more Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metrics. Products of cyhalothrin, a type II pyrethroid, include mixtures of isomers (e.g., λ-cyhalothrin) as well as enriched active isomers (e.g., γ-cyhalothrin). We measured acute changes in locomotor activity in adult male rats and directly correlated these changes to peak brain and plasma concentrations of λ- and γ-cyhalothrin using a within-subject design. One-hour locomotor activity studies were conducted 1.5h after oral gavage dosing, and immediately thereafter plasma and brains were collected for analyzing tissue levels using LC/MS/MS methods. Both isomers produced dose-related decreases in activity counts, and the effective dose range for γ-cyhalothrin was lower than for λ-cyhalothrin. Doses calculated to d...

Toxicology and Applied Pharmacology, Apr 30, 1991

A functional observational battery (FOB) was utilized to assess the effects of 3-day exposure to ... more A functional observational battery (FOB) was utilized to assess the effects of 3-day exposure to the formamidine pesticide amitraz in outbred Sprague-Dawleyderived and inbred Fischer-344-derived (F344) rats (both from Charles River Laboratories) and in outbred Long-Evans rats obtained from two commercial suppliers (Charles River Breeding Laboratories and Blue Spruce Farms). Significant strain and stock differences were obtained in baseline values for one-third of the FOB measures. In most cases, F344 rats were different from the others. Characteristic signs of amitraz exposure consisting of increased excitability, hyperreactivity, and physiological and autonomic changes were evident in all treated rats. These effects increased with repeated dosing, and many were still present 6 days after dosing. On individual measures, there were differences between the strains and stocks in terms of sensitivity and time course of amitraz effects. In general, Blue Spruce Long-Evans rats displayed more effects of amitraz and F344 rats recovered more quickly than others. Although Sprague-Dawley rats showed the least effect overall, they displayed the largest increases in the sensorimotor responses to stimuli. These data indicate that although some behavioral and physiological parameters showed strain and supplier differences, in both baseline values and the effects of amitraz, conclusions concerning its neurotoxic potential in a screening context would be similar. 0 1991 Academic PESS, IIK. ' The research described in this article has been supported by the U.S. Environmental Protection Agency Contract (No. 68-02-4450) to NSI Technology Services, Inc. This manuscript has been reviewed by the Health Effects Research Laboratory, U.S. E.P.A., and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ' Portions of this study were presented at the 29th annual

Toxicology, Feb 12, 2007

The Safe Drinking Water Act requires that the U.S. EPA consider noncancer endpoints for the asses... more The Safe Drinking Water Act requires that the U.S. EPA consider noncancer endpoints for the assessment of adverse human health effects of disinfection by-products (DBPs). As an extension of our studies in which we demonstrated neurotoxicity at relatively low levels of dibromo-and dichloroacetic acids, we examined the potential neurotoxicity of other classes of DBPs. Bromodichloromethane (BDCM) and dibromoacetonitrile (DBAN) were administered to male and female F-344 rats via drinking water for 6 months. During exposure, rats were tested for neurobehavioral effects using a functional observational battery and motor activity, followed by perfusion fixation for neuropathological evaluation at the end of exposure. Calculating for chemical loss, fluid consumption, and body weight, average intakes were approximately: 9, 27, and 72 mg/(kg day) BDCM, and 5, 12, and 29 mg/(kg day) DBAN. Fluid consumption was decreased in most treatment groups, but body weight gain was altered only at the high concentrations. There were few neurobehavioral changes, and these were not considered toxicologically relevant. Of the general observations, there was only minimally decreased body tone in DBAN-treated high-dose males. Treatment-related neuropathological findings were not observed. Lowered fluid consumption was the most sensitive and consistent endpoint in the present studies. Thus, unlike the haloacetic acids, neurotoxicity may not be a concern for toxicity of halomethanes or haloacetonitriles.