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Gene expression in developing brain is altered by modest reductions in circulating levels of thyroid hormone
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NBTS 2010 Abstract
NBTS28 Gene expression in developing brain is altered by modest reductions in circulating levels of thyroid hormone Mary Gilbert, Kevin Crofton, Gail Nelson, Geremy Knapp US Environmental Protection Agency, Research Triangle Park, NC, United States Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have not been adequately addressed. This research investigated dose– response relationships of TH insufficiency on TH action in developing brain. Three methods to perturb the thyroid axis were employed: propylthiouracil (PTU), dietary iodine deficiency, and perchlorate. PTU inhibits TH synthesis; iodine is an essential element for TH synthesis; and perchlorate is an environmental contaminant that blocks iodine uptake. These treatments were delivered via drinking water or food, producing graded levels of TH reduction during gestation and lactation. TH-responsive genes were examined in cortex of offspring on PN14. A set of 8 genes that were significantly altered in a gene array analysis by PTU was selected based on the magnitude of change, significance to brain development, and link to thyroid function. Gene-expression was determined using qRT-PCR and used as an estimate of TH action, i.e., an indication of adequate levels of TH in critical target tissues. Dose-dependent reductions in expression of a number of genes were observed that were similar across different modes of thyroid-axis perturbation. Significant reductions were also observed at doses that produced mild reductions in circulating TH in dams or offspring. These findings suggest that autoregulatory mechanisms of the thyroid axis may be insufficient to maintain required tissue levels of TH in the developing brain. (Does not necessarily reflect EPA policy.) doi:10.1016/j.ntt.2010.04.029
NBTS29 Outcome in mice exposed in utero to chlorpyrifos Thomas M. Burbacher, Toby B. Cole, Jenna Fisher, Sarah Park, Sungwoo Hong, William C. Griffith, Elaine M. Faustman Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA Pregnant C57Bl/6J mice were injected subcutaneously daily from GD6 to GD17 with chlorpyrifos (dissolved in DMSO) at 0, 2, 4, or 12 mg/kg/day. Control mice received DMSO alone. Experiments were conducted in three cohorts as part of a larger study that examined other endpoints of toxicity (global gene expression and acetylcholinesterase activity in dams and fetuses). On postnatal day 4 after parturition, litters were culled to six mice (3 males and 3 females). One male and one female from each litter were assigned randomly to “neurobehavioral assessment group A” and one male and one female were assigned to “neurobehavioral assessment group B”, with the remaining two mice used for measurement of brain acetylcholinesterase activity. At weaning, mice were transferred to the neurobehavioral testing facility and housed two per cage for the duration of testing. No overt signs of cholinergic toxicity, such as tremors or difficulty breathing, were observed in pregnant females or offspring. Postnatal weight gain was significantly reduced in chlorpyrifosexposed offspring. Chlorpyrifos exposure delayed reflex righting but accelerated negative geotaxis behavior. A gender specific effect of chlorpyrifos exposure was observed on cued fear conditioning. Male
offspring exposed to chlorpyrifos exhibited lower response rates (% freezing) to the cue (tone) than controls. Chlorpyrifos exposure affected Morris maze acquisition, retention and reversal. Most effects were observed at the 12 mg/kg/day dosage. The results indicate that chlorpyrifos affects a wide range of developmental processes. (Supported by CHC grants 5-P01-ES009601 NIEHS/NIH and RD83170901-0 EPA and CEEH grant 5 P30 ES07033 NIEHS.) doi:10.1016/j.ntt.2010.04.030
NBTS30 Effects of methylphenidate on motivation in children with attention-deficit/hyperactivity disorder John Chelonisa,b, Teresa Johnsonb, Sherry Fergusona,b, Brian Kubacakb, Mark Edwardsb, Merle Paulea,b a National Center for Toxicological Research-FDA, Jefferson, AR, United States b University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock, AR, United States This research examined the effects of methylphenidate (MPH) on motivation in children who were prescribed MPH for the treatment of ADHD using a progressive ratio (PR) task. Twenty-three children 7 to 12 years of age completed two test sessions, one on medication and one off. During each session, children pressed a lever to earn nickel reinforcers, where the first press resulted in a reinforcer and ten additional presses were required for each subsequent reinforcer. Children on MPH made significantly more responses during than when off medication. This MPH-associated response increase was reflected in a significant decrease in the inter-response times (IRT). Further, MPH administration resulted in a significant decrease in the variability of IRTs. In contrast, the MPH administration had no significant effects on the means and variability of post-reinforcement pause durations. These results suggest that MPH increased motivation in children being treated for ADHD. However, the inability of MPH to significantly reduce post-reinforcement pauses while simultaneously decreasing IRTs suggests that while MPH may increase motivation to perform an ongoing task, it may have little effect on the initiation of a task. doi:10.1016/j.ntt.2010.04.031
NBTS31 Effect of lifetime exposure to acrylamide on motor nerve conduction velocity in rats at one year of age Joan Gareya, Zbigniew Biniendab, Merle Pauleb a SRC, Inc, Arlington, VA, United States b NCTR/FDA, Jefferson, AR, United States The ability of acrylamide (ACR) to alter motor nerve conduction velocity (CV) in rats was addressed as part of a lifetime ACR exposure study. Reduction in CV among treated animals is considered a sensitive method for detecting the presence of ACR-induced neuropathy in the absence of clearly identifiable locomotor dysfunction. We previously established a method of measuring CV in which changes in CV were observed in rats dosed (i.p.) with 30 mg/kg bw ACR daily over two weeks; i.e., a statistically significantly lower CV was observed in ACRtreated rats compared with control rats. In the current study, Fischer 344 rats were treated with ACR from gestational day 6 (dams were gavaged with 0, 0.1, 0.3, 1.0 or 5.0 mg/kg bw/day) through parturition.
NBTS 2010 Abstract
NBTS28 Gene expression in developing brain is altered by modest reductions in circulating levels of thyroid hormone Mary Gilbert, Kevin Crofton, Gail Nelson, Geremy Knapp US Environmental Protection Agency, Research Triangle Park, NC, United States Disruption of thyroid hormone (TH) homeostasis is a known effect of environmental contaminants. Although animal models of developmental TH deficiency can predict the impact of severe insults to the thyroid system, the effects of moderate TH insufficiencies have not been adequately addressed. This research investigated dose– response relationships of TH insufficiency on TH action in developing brain. Three methods to perturb the thyroid axis were employed: propylthiouracil (PTU), dietary iodine deficiency, and perchlorate. PTU inhibits TH synthesis; iodine is an essential element for TH synthesis; and perchlorate is an environmental contaminant that blocks iodine uptake. These treatments were delivered via drinking water or food, producing graded levels of TH reduction during gestation and lactation. TH-responsive genes were examined in cortex of offspring on PN14. A set of 8 genes that were significantly altered in a gene array analysis by PTU was selected based on the magnitude of change, significance to brain development, and link to thyroid function. Gene-expression was determined using qRT-PCR and used as an estimate of TH action, i.e., an indication of adequate levels of TH in critical target tissues. Dose-dependent reductions in expression of a number of genes were observed that were similar across different modes of thyroid-axis perturbation. Significant reductions were also observed at doses that produced mild reductions in circulating TH in dams or offspring. These findings suggest that autoregulatory mechanisms of the thyroid axis may be insufficient to maintain required tissue levels of TH in the developing brain. (Does not necessarily reflect EPA policy.) doi:10.1016/j.ntt.2010.04.029
NBTS29 Outcome in mice exposed in utero to chlorpyrifos Thomas M. Burbacher, Toby B. Cole, Jenna Fisher, Sarah Park, Sungwoo Hong, William C. Griffith, Elaine M. Faustman Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA Pregnant C57Bl/6J mice were injected subcutaneously daily from GD6 to GD17 with chlorpyrifos (dissolved in DMSO) at 0, 2, 4, or 12 mg/kg/day. Control mice received DMSO alone. Experiments were conducted in three cohorts as part of a larger study that examined other endpoints of toxicity (global gene expression and acetylcholinesterase activity in dams and fetuses). On postnatal day 4 after parturition, litters were culled to six mice (3 males and 3 females). One male and one female from each litter were assigned randomly to “neurobehavioral assessment group A” and one male and one female were assigned to “neurobehavioral assessment group B”, with the remaining two mice used for measurement of brain acetylcholinesterase activity. At weaning, mice were transferred to the neurobehavioral testing facility and housed two per cage for the duration of testing. No overt signs of cholinergic toxicity, such as tremors or difficulty breathing, were observed in pregnant females or offspring. Postnatal weight gain was significantly reduced in chlorpyrifosexposed offspring. Chlorpyrifos exposure delayed reflex righting but accelerated negative geotaxis behavior. A gender specific effect of chlorpyrifos exposure was observed on cued fear conditioning. Male
offspring exposed to chlorpyrifos exhibited lower response rates (% freezing) to the cue (tone) than controls. Chlorpyrifos exposure affected Morris maze acquisition, retention and reversal. Most effects were observed at the 12 mg/kg/day dosage. The results indicate that chlorpyrifos affects a wide range of developmental processes. (Supported by CHC grants 5-P01-ES009601 NIEHS/NIH and RD83170901-0 EPA and CEEH grant 5 P30 ES07033 NIEHS.) doi:10.1016/j.ntt.2010.04.030
NBTS30 Effects of methylphenidate on motivation in children with attention-deficit/hyperactivity disorder John Chelonisa,b, Teresa Johnsonb, Sherry Fergusona,b, Brian Kubacakb, Mark Edwardsb, Merle Paulea,b a National Center for Toxicological Research-FDA, Jefferson, AR, United States b University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock, AR, United States This research examined the effects of methylphenidate (MPH) on motivation in children who were prescribed MPH for the treatment of ADHD using a progressive ratio (PR) task. Twenty-three children 7 to 12 years of age completed two test sessions, one on medication and one off. During each session, children pressed a lever to earn nickel reinforcers, where the first press resulted in a reinforcer and ten additional presses were required for each subsequent reinforcer. Children on MPH made significantly more responses during than when off medication. This MPH-associated response increase was reflected in a significant decrease in the inter-response times (IRT). Further, MPH administration resulted in a significant decrease in the variability of IRTs. In contrast, the MPH administration had no significant effects on the means and variability of post-reinforcement pause durations. These results suggest that MPH increased motivation in children being treated for ADHD. However, the inability of MPH to significantly reduce post-reinforcement pauses while simultaneously decreasing IRTs suggests that while MPH may increase motivation to perform an ongoing task, it may have little effect on the initiation of a task. doi:10.1016/j.ntt.2010.04.031
NBTS31 Effect of lifetime exposure to acrylamide on motor nerve conduction velocity in rats at one year of age Joan Gareya, Zbigniew Biniendab, Merle Pauleb a SRC, Inc, Arlington, VA, United States b NCTR/FDA, Jefferson, AR, United States The ability of acrylamide (ACR) to alter motor nerve conduction velocity (CV) in rats was addressed as part of a lifetime ACR exposure study. Reduction in CV among treated animals is considered a sensitive method for detecting the presence of ACR-induced neuropathy in the absence of clearly identifiable locomotor dysfunction. We previously established a method of measuring CV in which changes in CV were observed in rats dosed (i.p.) with 30 mg/kg bw ACR daily over two weeks; i.e., a statistically significantly lower CV was observed in ACRtreated rats compared with control rats. In the current study, Fischer 344 rats were treated with ACR from gestational day 6 (dams were gavaged with 0, 0.1, 0.3, 1.0 or 5.0 mg/kg bw/day) through parturition.