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Alteration of juvenile rat emotional behavior and social play following preweanling exposure to inhibitors of FAAH
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NBTS / INA 2015 Abstracts
the traumatic effects of impulse noise on the organ of Corti were enhanced by co-exposure to styrene, even at the lower concentration of styrene. The results showed also that the noise spectrum defined the location of the cochlear trauma caused by combined exposure. The tonotopicity of the styrene-induced damage depended on the associated noise spectrum, what complicates diagnosis of styrenerelated hearing loss with a tone–frequency audiometric approach. In conclusion, there is not a frequency specificity of impairments due to styrene. Based on the present results, the temporal structure of the noise should be reintroduced as a key parameter in hearing conservation regulations. doi:10.1016/j.ntt.2015.04.067
NTX62 Alteration of juvenile rat emotional behavior and social play following preweanling exposure to inhibitors of FAAH R.L. Carr, N.H. Armstrong, A.T. Buhanan, K.A. De Leon, J.B. Eells, L. Loyant, A.N. Mohammed, M.K. Ross, C.A. Nail Mississippi State University, Mississippi City, MS, USA Repeated developmental exposure to the organophosphorus (OP) insecticide chlorpyrifos (CPF) results in the inhibition of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide (AEA), and leads to the accumulation of AEA in the forebrain. At lower dosages, this occurs without measurable inhibition of cholinesterase (ChE), which is the canonical target of CPF. This suggests that the endocannabinoid system may be an important target in the developmental toxicity of OP insecticides. However, it is not clear if these biochemical changes during development will result in functional effects as the animal ages. To investigate this, rat pups were exposed daily by oral gavage to either 0.5, 0.75, or 1.0 mg/kg CPF from postnatal day (PND) 10–16 and behaviors related to the endocannabinoid system were monitored. In our initial experiment, rats were placed into a dark container in a novel open field and the latency to emerge from the container was measured. All CPF treated groups spent significantly less time in the dark prior to emerging as compared to control suggesting a decreased level of emotional reactivity induced by CPF exposure (PND25). In a subsequent experiment, an additional treatment group received 0.02 mg/kg PF-04457845, a specific inhibitor of FAAH. In the open field (PND23), the high CPF and PF-04457845 groups exhibited increased motor activity but no differences in the time spent in the field's center. In the elevated plus maze (PND29), all three CPF dosage groups and the PF-04457845 group had increased % entries into the open arms and % time spent in the open arms. On PND36, social behavior was monitored and all three CPF dosage groups and the PF04457845 group spent more time playing than did controls. The similarities in behavior between PF-04457845 and CPF suggest that developmental inhibition of FAAH could be responsible for the altered behavior induced by developmental CPF exposure. doi:10.1016/j.ntt.2015.04.068
NTX63 Low-dose paraquat exposure inhibits cell proliferation and induced apoptosis in human neural progenitor cells Xiuli Chang, Tingting Dou, Xinjin Wang, Zhijun Zhou Fudan University, Shanghai, China Extensive evidence demonstrates that exogenous chemicals could affect normal development of nervous system by interfering proliferation
of neural stem cells, in which cell cycle and apoptosis play an important role. Paraquat (PQ) is a widely studied neurotoxicant that perturbs the normal structure/function of adult CNS. However, the impacts of PQ exposure on the developing nervous system remain unclear. In this study, we observed effects of oxidative stress caused by PQ on immortalized human embryonic neural progenitor cells (hNPCs) by treating them with various concentrations of PQ (1 μM, and 10 μM). We found that PQ had no adverse effect on cell viability but reduced NSC proliferation and altered the expression of cell cycle regulators (p53, p16 and p21). These changes were observed in cells directly exposed to PQ (parent cells) and in their daughter cells cultured under PQ-free conditions. In addition, PQ induced apoptosis, reactive oxygen species (ROS) production and increased the lipid peroxidation marker MDA level in a dose-dependent manner after 24 h PQ treatment. Meanwhile, mediators of programmed cell death, caspase3 and caspase9, were increased significantly at 1 μM and 10 μM of PQ, respectively. Similarly, PQ triggered cytochrome C releases at the concentration of 10 μM. These results suggest that PQ via enhanced oxidative stress could significantly reduce proliferation of hNPCs at the dose causing no decrease of cell viability and the inhibition could last in daughter cells. Besides, PQ could induce early and late apoptosis by activation of mitochondrial pathway. This research was supported by the National Natural Science Foundation of China (No: 81472996). doi:10.1016/j.ntt.2015.04.069
NTX64 Neurodevelopmental effects of manganese and lead co-exposure: A case study of teeth as a novel exposure biomarker Birgit Claus Henna,c, Brent A. Coullb,c a Boston University School of Public Health, Boston, MA, USA b Harvard University School of Public Health, Cambridge, MA, USA c Icahn School of Medicine at Mount Sinai, New York, NY, USA Our current understanding of the health effects of Pb and Mn coexposures is based largely on metal levels measured in blood. However, there may be substantial exposure misclassification, given the short half-life of Mn in blood. A preferred biomarker would be an integrated exposure measure that reflects specific windows of development. The tooth biomarker is such a measure, which can provide information on exposure timing and can be used to identify critical windows to individual chemicals and mixtures. We collected 125 teeth from Mexican children enrolled in a prospective birth cohort and analyzed teeth for Mn and Pb concentrations, reflecting prenatal through early postnatal (0–12 months) exposures. We measured visual motor ability, an aspect of cognitive ability, among these children using the Wide Range Assessment of Visual Motor Abilities (WRAVMA). Individual and interactive effects of Mn and Pb on visual motor ability were estimated using multivariable regression models and distributed lag models. Tooth Mn measurements at prenatal time points were positively associated with visual motor ability (adjusted βs, 2nd trimester = 3.9 [−2.6, 10.4]; 3rd trimester = 2.3 [95% CI: −3.0, 7.5]). However, at postnatal time points, negative slopes were observed (adjusted βs, ≤6 months = − 2.1 [− 7.1, 2.9]; N6 months = − 4.0 [− 12.7, 2.9]). The Mn-visual motor ability association changed markedly when considering co-exposure to Pb: at high Pb levels (tooth Pb N median), the positive association with visual motor ability during the prenatal period was attenuated; postnatally, Mn was significantly inversely associated with visual motor ability in children who have higher Pb levels (p = 0.003). Associations between Mn exposure, measured in teeth, and visual motor ability varied by exposure timing, supporting the notion of
NBTS / INA 2015 Abstracts
the traumatic effects of impulse noise on the organ of Corti were enhanced by co-exposure to styrene, even at the lower concentration of styrene. The results showed also that the noise spectrum defined the location of the cochlear trauma caused by combined exposure. The tonotopicity of the styrene-induced damage depended on the associated noise spectrum, what complicates diagnosis of styrenerelated hearing loss with a tone–frequency audiometric approach. In conclusion, there is not a frequency specificity of impairments due to styrene. Based on the present results, the temporal structure of the noise should be reintroduced as a key parameter in hearing conservation regulations. doi:10.1016/j.ntt.2015.04.067
NTX62 Alteration of juvenile rat emotional behavior and social play following preweanling exposure to inhibitors of FAAH R.L. Carr, N.H. Armstrong, A.T. Buhanan, K.A. De Leon, J.B. Eells, L. Loyant, A.N. Mohammed, M.K. Ross, C.A. Nail Mississippi State University, Mississippi City, MS, USA Repeated developmental exposure to the organophosphorus (OP) insecticide chlorpyrifos (CPF) results in the inhibition of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide (AEA), and leads to the accumulation of AEA in the forebrain. At lower dosages, this occurs without measurable inhibition of cholinesterase (ChE), which is the canonical target of CPF. This suggests that the endocannabinoid system may be an important target in the developmental toxicity of OP insecticides. However, it is not clear if these biochemical changes during development will result in functional effects as the animal ages. To investigate this, rat pups were exposed daily by oral gavage to either 0.5, 0.75, or 1.0 mg/kg CPF from postnatal day (PND) 10–16 and behaviors related to the endocannabinoid system were monitored. In our initial experiment, rats were placed into a dark container in a novel open field and the latency to emerge from the container was measured. All CPF treated groups spent significantly less time in the dark prior to emerging as compared to control suggesting a decreased level of emotional reactivity induced by CPF exposure (PND25). In a subsequent experiment, an additional treatment group received 0.02 mg/kg PF-04457845, a specific inhibitor of FAAH. In the open field (PND23), the high CPF and PF-04457845 groups exhibited increased motor activity but no differences in the time spent in the field's center. In the elevated plus maze (PND29), all three CPF dosage groups and the PF-04457845 group had increased % entries into the open arms and % time spent in the open arms. On PND36, social behavior was monitored and all three CPF dosage groups and the PF04457845 group spent more time playing than did controls. The similarities in behavior between PF-04457845 and CPF suggest that developmental inhibition of FAAH could be responsible for the altered behavior induced by developmental CPF exposure. doi:10.1016/j.ntt.2015.04.068
NTX63 Low-dose paraquat exposure inhibits cell proliferation and induced apoptosis in human neural progenitor cells Xiuli Chang, Tingting Dou, Xinjin Wang, Zhijun Zhou Fudan University, Shanghai, China Extensive evidence demonstrates that exogenous chemicals could affect normal development of nervous system by interfering proliferation
of neural stem cells, in which cell cycle and apoptosis play an important role. Paraquat (PQ) is a widely studied neurotoxicant that perturbs the normal structure/function of adult CNS. However, the impacts of PQ exposure on the developing nervous system remain unclear. In this study, we observed effects of oxidative stress caused by PQ on immortalized human embryonic neural progenitor cells (hNPCs) by treating them with various concentrations of PQ (1 μM, and 10 μM). We found that PQ had no adverse effect on cell viability but reduced NSC proliferation and altered the expression of cell cycle regulators (p53, p16 and p21). These changes were observed in cells directly exposed to PQ (parent cells) and in their daughter cells cultured under PQ-free conditions. In addition, PQ induced apoptosis, reactive oxygen species (ROS) production and increased the lipid peroxidation marker MDA level in a dose-dependent manner after 24 h PQ treatment. Meanwhile, mediators of programmed cell death, caspase3 and caspase9, were increased significantly at 1 μM and 10 μM of PQ, respectively. Similarly, PQ triggered cytochrome C releases at the concentration of 10 μM. These results suggest that PQ via enhanced oxidative stress could significantly reduce proliferation of hNPCs at the dose causing no decrease of cell viability and the inhibition could last in daughter cells. Besides, PQ could induce early and late apoptosis by activation of mitochondrial pathway. This research was supported by the National Natural Science Foundation of China (No: 81472996). doi:10.1016/j.ntt.2015.04.069
NTX64 Neurodevelopmental effects of manganese and lead co-exposure: A case study of teeth as a novel exposure biomarker Birgit Claus Henna,c, Brent A. Coullb,c a Boston University School of Public Health, Boston, MA, USA b Harvard University School of Public Health, Cambridge, MA, USA c Icahn School of Medicine at Mount Sinai, New York, NY, USA Our current understanding of the health effects of Pb and Mn coexposures is based largely on metal levels measured in blood. However, there may be substantial exposure misclassification, given the short half-life of Mn in blood. A preferred biomarker would be an integrated exposure measure that reflects specific windows of development. The tooth biomarker is such a measure, which can provide information on exposure timing and can be used to identify critical windows to individual chemicals and mixtures. We collected 125 teeth from Mexican children enrolled in a prospective birth cohort and analyzed teeth for Mn and Pb concentrations, reflecting prenatal through early postnatal (0–12 months) exposures. We measured visual motor ability, an aspect of cognitive ability, among these children using the Wide Range Assessment of Visual Motor Abilities (WRAVMA). Individual and interactive effects of Mn and Pb on visual motor ability were estimated using multivariable regression models and distributed lag models. Tooth Mn measurements at prenatal time points were positively associated with visual motor ability (adjusted βs, 2nd trimester = 3.9 [−2.6, 10.4]; 3rd trimester = 2.3 [95% CI: −3.0, 7.5]). However, at postnatal time points, negative slopes were observed (adjusted βs, ≤6 months = − 2.1 [− 7.1, 2.9]; N6 months = − 4.0 [− 12.7, 2.9]). The Mn-visual motor ability association changed markedly when considering co-exposure to Pb: at high Pb levels (tooth Pb N median), the positive association with visual motor ability during the prenatal period was attenuated; postnatally, Mn was significantly inversely associated with visual motor ability in children who have higher Pb levels (p = 0.003). Associations between Mn exposure, measured in teeth, and visual motor ability varied by exposure timing, supporting the notion of