ProjectDevelopmental Neurotoxicity of Superfund Pesticide: Biomarkers and Mechanisms
Project Leader: Theodore A. Slotkin
Publications ↓Project Description
Organophosphate (OP) pesticides are used worldwide and are a Superfund disposal problem. In the previous period, Dr. Slotkin and his research team showed that chlorpyrifos is a developmental neurotoxicant that acts over a window extending from the rudiments of brain formation all the way through late postnatal stages. Importantly, these adverse effects are exerted by a family of mechanisms in addition to cholinesterase inhibition, the process that mediates adult systemic toxicity. This raises two important questions: what types of biomarkers can be used to characterize the mechanisms underlying developmental neurotoxicity of these agents, and how do we assess related and unrelated toxicants for the same types of effects? There are four aims:
- To identify cellular/molecular mechanisms underlying the developmental neurotoxicity of chlorpyrifos: the basic machinery of neural cell replication/differentiation, selection of transmitter phenotype, signal transduction, axonogenesis, oxidative stress, apoptosis, functional responses.
- To compare the mechanisms for chlorpyrifos with those of other OPs and non-OP
cholinesterase inhibitors (physostigmine): are all OPs or cholinesterase inhibitors the same? - To use the same approach to evaluate the developmental neurotoxicity of other Superfund chemicals (also studied in other projects): dieldrin, nickel, Elizabeth River Sediment Extracts, chlorpyrifos photolytic products. Can the PC12 model be used to screen neurotoxicants?
- To develop a genomic array "fingerprint" for vulnerability to neurotoxicity in different phases of cell development, with a link to specific phenotypes and endpoints. Evaluations of time dependent changes in gene clusters for cell cycle, differentiation, neurotransmitter phenotype, oxidative stress, apoptosis for different developmental phases (undifferentiated, early differentiation, terminal differentiation), for selected toxicants with related (chlorpyrifos, parathion) or unrelated (nickel, dieldrin) mechanisms.
Description ↑Publications
Slotkin TA, Ryde IT and Seidler FJ. 2010. Additive and synergistic effects of fetal nicotine and dexamethasone exposure on cholinergic synaptic function in adolescence and adulthood: implications for the adverse consequences of maternal smoking and pharmacotherapy of preterm delivery. Brain Res. Bull. 81:552-560.
Adigun AA, Seidler FJ and Slotkin TA. 2010. Disparate developmental neurotoxicants converge on the cyclic AMP signaling cascade, revealed by transcriptional profiles in vitro and in vivo. Brain Res. 1316:1-16.
Dotan S, Goldstein RS, Slotkin TA and Yanai J. 2010. An avian model for the reversal of neurobehavioral teratogenicity with neural stem cells. Neurotoxicol. Teratol. :in press.
Kreider ML, Tate CA, Cousins MM, Oliver CA, Seidler FJ and Slotkin TA. 2006. Lasting effects of developmental dexamethasone treatment on neural cell number and size, synaptic activity and cell signaling: critical periods of vulnerability, dose-effect relationships, regional targets and sex selectivity. Neuropsychopharmacology 31:12-35.
Slotkin TA and Seidler FJ. 2009. Benzo[a]pyrene impairs neurodifferentiation in PC12 cells. Brain Res. Bull. 80:17-21. PMC2717353
Slotkin TA and Seidler FJ. 2010. Mimicking maternal smoking and pharmacotherapy of preterm labor: interactions of fetal nicotine and dexamethasone on serotonin and dopamine synaptic function in adolescence and adulthood. Brain Res. Bull. :in press. PMC In Process
Slotkin TA, Bodwell BE, Levin ED and Seidler FJ. 2008. Neonatal exposure to low doses of diazinon: long-term effects on neural cell development and acetylcholine systems. Environ. Health Perspect. 116:340-348. PMC2265026
Slotkin TA, Bodwell BE, Ryde IT, Levin ED and Seidler FJ. 2008. Exposure of neonatal rats to parathion elicits sex-selective impairment of acetylcholine systems in brain regions during adolescence and adulthood. Environ. Health Perspect. 116:1308-1314. PMC2569087
Slotkin TA, Levin ED and Seidler FJ. 2009. Developmental neurotoxicity of parathion: progressive effects on serotonergic systems in adolescence and adulthood. Neurotoxicol. Teratol. 31:11-17. PMC2630364
Slotkin TA, Ryde IT, Levin ED and Seidler FJ. 2008. Developmental neurotoxicity of low-dose diazinon exposure of neonatal rats: effects on serotonin systems in adolescence and adulthood. Brain Res. Bull. 75:640-647. PMC2322865
Buznikov, G.A., L.A. Nikitina, L.M. Rakić, I. Milošević, V.V. Bezuglov, J.M. Lauder and T.A. Slotkin. 2007. The sea urchin embryo, an invertebrate model for mammalian developmental neurotoxicity, reveals multiple neurotransmitter mechanisms for effects of chlorpyrifos: therapeutic interventions and a comparison with the monoamine depleter, reserpine. Brain Research Bulletin. 74: 221-231.
Slotkin, T.A., E.A. MacKillop, I.T. Ryde and F.J. Seidler. 2007. Ameliorating the developmental neurotoxicity of chlorpyrifos: a mechanisms-based approach in PC12 cells. Environmental Health Perspectives. 115: 1306-1313.
Slotkin, T.A. and F.J. Seidler. 2007. Developmental exposure to terbutaline and chlorpyrifos, separately or sequentially, elicits presynaptic serotonergic hyperactivity in juvenile and adolescent rats. Brain Research Bulletin. 73: 301-309.
Slotkin, T.A., F.J. Seidler and F. Fumagalli. 2007. Exposure to organophosphates reduces the expression of neurotrophic factors in neonatal rat brain regions: similarities and differences in the effects of chlorpyrifos and diazinon on the fibroblast growth factor superfamily. Environmental Health Perspectives. 115: 909-916.
Slotkin, T.A. and F.J. Seidler. 2007. Comparative developmental neurotoxicity of organophosphates in vivo: transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems. Brain Research Bulletin. 72: 232-274.
Slotkin, T.A. and F.J. Seidler. 2007. Prenatal chlorpyrifos exposure elicits presynaptic serotonergic and dopaminergic hyperactivity at adolescence: critical periods for regional and sex-selective effects. Reproductive Toxicology. 23: 421-427.
Jameson, R.R., F.J. Seidler and T.A. Slotkin. 2007. Nonenzymatic functions of acetylcholinesterase splice variants in the developmental neurotoxicity of organophosphates: chlorpyrifos, chlorpyrifos oxon and diazinon. Environmental Health Perspectives. 115: 65-70.
Slotkin , T.A., E.A. MacKillop, I.T. Ryde, C.A. Tate and F.J. Seidler. 2007. Screening for developmental neurotoxicity using PC12 cells: comparisons of organophosphates with a carbamate, an organochlorine and divalent nickel. Environmental Health Perspectives. 115: 93-101.
Slotkin, T.A., E.D. Levin and F.J. Seidler. 2006. Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity. Environmental Health Perspectives. 114: 746-751.
Jameson, R.R., F.J. Seidler, D. Qiao and T.A. Slotkin. 2006. Chlorpyrifos affects phenotypic outcomes in a model of mammalian neurodevelopment: critical stages targeting differentiation in PC12 cells. Environmental Health Perspectives. 114: 667-672.
Slotkin, T.A. 2005. Developmental neurotoxicity of organophosphates: a case study of chlorpyrifos, in \"Toxicity of Organophosphate and Carbamate Pesticides\" (R.C. Gupta, ed.), pp. 293-314, Elsevier Academic Press, San Diego.
Slotkin, T.A., C.A. Tate, M.M. Cousins and F.J. Seidler. 2005. Imbalances emerge in cardiac autonomic cell signaling after neonatal exposure to terbutaline or chlorpyrifos, alone or in combination. Developmental Brain Research. 160: 219-230.
Slotkin, T.A., K.K. Brown and F.J. Seidler. 2005. Developmental exposure of rats to chlorpyrifos elicits sex-selective hyperlipidemia and hyperinsulinemia in adulthood. Environmental Health Perspectives. 113: 1291-1294.
Aldridge, J.E., A. Meyer, F.J. Seidler and T.A. Slotkin. 2005. Alterations in central nervous system serotonergic and dopaminergic synaptic activity in adulthood after prenatal or neonatal chlorpyrifos exposure. Environmental Health Perspectives. 113: 1027-1035.
Aldridge, J.E., E.D. Levin, F.J. Seidler and T.A. Slotkin. 2005. Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, resembling animal models of depression and involving serotonergic mechanisms. Environmental Health Perspectives. 113: 527-531.
Garcia, S.J., F.J. Seidler and T.A. Slotkin. 2005. Developmental neurotoxicity of chlorpyrifos: targeting glial cells. Environmental Toxicology and Pharmacology. 19: 455-465.
Aldridge, Justin E., Armando Meyer, Fredric J. Seidler, and Theodore A. Slotkin. 2005. Developmental exposure to terbutaline and chlorpyrifos: pharmacotherapy of preterm labor and an environmental neurotoxicant converge on serotonergic systems in neonatal rat brain regions. Toxicology and Applied Pharmacology. 203(2):132-144.
Meyer, Armando, Fredric J. Seidler, Justin E. Aldridge, and Theodore A. Slotkin. 2005. Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos. Toxicology and Applied Pharmacology. 203(2):154-166.
Qiao, Dan, Fredric J. Seidler, and Theodore A. Slotkin. 2005. Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos. Toxicology and Applied Pharmacology. 206(1):17-.
Roy, Tara Sankar, Vikram Sharma, Fredric J. Seidler, and Theodore A. Slotkin. 2005. Quantitative morphological assessment reveals neuronal and glial deficits in hippocampus after a brief subtoxic exposure to chlorpyrifos in neonatal rats. Developmental Brain Research. 155(1):71-80.
Slotkin, Theodore A. and Fredric J. Seidler. 2005. The alterations in CNS serotonergic mechanisms caused by neonatal chlorpyrifos exposure are permanent. Developmental Brain Research. 158(1-2):115-119.
Slotkin, Theodore A., Colleen A. Oliver, and Fredric J. Seidler. 2005. Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination. Developmental Brain Research. 157(2):172-180.
Aldridge, Justin E., Fredric J. Seidler, and Theodore Slotkin. 2004. Developmental Exposure to Chlorpyrifos Elicits Sex-Selective Alterations of Serotonergic Synaptic Function in Adulthood: Critical Periods and Regional Selectivity for Effects on the Serotonin Transporter, Receptor Subtypes, and Cell Signaling. Environmental Health Perspectives. 112(2):148-155.
Iceogle, Laura M., N. Channelle Christopher, W. Paul Blackwelder, D. Patrick Caldwell, Dan Qiao, Fredric J. Seidler, Theodore Slotkin, and Edward Levin. 2004. Behavioral alterations in adolescent and adult rats caused by a brief subtoxic exposure to chlorpyrifos during neurulation. Neurotoxicology and Teratology. 26(1):95-101.
Izrael, Michal, Eddy A. Van der Zee, Theodore A. Slotkin, and Joseph Yanai. 2004. Cholinergic synaptic signaling mechanisms underlying behavioral teratogenicity: effects of nicotine, chlorpyrifos, and heroin converge on protein kinase C translocation in the intermedial part of the hyperstriatum ventrale and on imprinting behavior in an avian model. Journal of Neuroscience Research. 78(4):499-507.
Meyer, Armando, Fredric J. Seidler, Justin E. Aldridge, Charlotte A. Tate, Mandy M. Cousins, and Theodore Slotkin. 2004. Critical Periods for Chlorpyrifos-Induced Developmental Neurotoxicity: Alterations in Adenylyl Cyclase Signaling in Adult Rat Brain Regions after Gestational or Neonatal Exposure. Environmental Health Perspectives. 112(3):295-301.
Meyer, Armando, Fredric J. Seidler, and Theodore Slotkin. 2004. Developmental Effects of Chlorpyrifos Extend Beyond Neurotoxicity: Critical Periods for Immediate and Delayed-Onset Effects on Cardiac and Hepatic Cell Signaling. Environmental Health Perspectives. 112(2):170-178.
Qiao, Dan, Fredric J. Seidler, Yael Abreu-Villaca, Charlotte A. Tate, Mandy M. Cousins, and Theodore Slotkin. 2004. Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood. Developmental Brain Research. 148(1):43-52.
Qiao, Dan, Fredric J. Seidler, J.D. Violin, and Theodore Slotkin. 2004. Nicotine is a developmental neurotoxicant and neuroprotectant: stage-selective inhibition of DNA synthesis coincident with shielding from effects of chlorpyrifos. Developmental Brain Research. 147(1-2):183-190.
Rhodes, M.C., Fredric J. Seidler, Charlotte A. Tate, Mandy M. Cousins, and Theodore Slotkin. 2004. Does pharmacotherapy for preterm labor sensitize the developing brain to environmental neurotoxicants? Cellular and synaptic effects of sequential exposure to terbutaline and chlorpyrifos in neonatal rats. Toxicology and Applied Pharmacology. 195(2):203-217.
Roy, Tara Sankar, Fredric J. Seidler, and Theodore Slotkin. 2004. Morphologic effects of subtoxic neonatal chlorpyrifos exposure in developing rat brain: regionally selective alterations in neurons and glia. Developmental Brain Research. 148(2):197-206.
Slotkin, Theodore. 2004. Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates. Toxicology and Applied Pharmacology. 198:132-151.
Slotkin, Theodore. 2004. Guidelines for developmental neurotoxicity and their impact on organophosphate pesticides: a personal view from an academic perspective. NeuroToxicology. 25(4):631-640.
Aldridge, J.E., F.J. Seidler, A. Meyer, I. Thillai, and Theodore Slotkin. 2003. Serotonergic systems targeted by developmental exposure to chlorpyrifos: effects during different critical periods. Environmental Health Perspectives. 111(14):1736-1743.
Buznikov, G.A., Theodore Slotkin, and J.M. Lauder. 2003. Sea urchin embryos and larvae as biosensors for neurotoxins. In: Current Protocals in Toxicology. John Wiley & Sons, NY. pp.1.6.1-1.6.24.
Dam, K., F.J. Seidler, and Theodore Slotkin. 2003. Transcriptional biomarkers distinguish between vunerable periods for developmental neurotoxicity of chlorpyrifos: implications for toxicogenomics. Brain Research Bulletin. 59:261-265.
Garcia, S.J., F.J. Seidler, and Theodore Slotkin. 2003. Developmental neurotoxicity elicited by prenatal or postnatal chlorpyrifos exposure: effects on neurospecific proteins indicate changing vulnerabilities. Environmental Health Perspectives. 111(3):297-303.
Meyer, A., F.J. Seidler, M.M. Cousins, and Theodore Slotkin. 2003. Developmental Neurotoxicity Elicited by Gestational Exposure to Chlorpyrifos: When Is Adenylyl Cyclase a Target?. Environmental Health Perspectives. 111(16):1871-1876.
Qiao, D., L.A. Nikitina, G.A. Buznikov, J.M. Lauder, F.J. Seidler, and Theodore Slotkin. 2003. The sea urchin embryo as a model for mammalian developmental neurotoxicity: ontogenesis of the high-affinity choline transporter and its role in cholinergic trophic activity. Environmental Health Perspectives. 111(14):536-544.
Qiao, D., F.J. Seidler, C.A. Tate, M.M. Cousins, and Theodore Slotkin. 2003. Fetal chlorpyrifos exposure: adverse effects on brain cell development and cholinergic biomarkers emerge postnatally and continue into adolescence and adulthood. Environmental Health Perspectives. 111(4):536-544.
Qiao, Dan, Lyudmila A. Nikitina, Gennady A. Buznikov, Jean M. Lauder, Fredric J. Seidler, and Theodore Slotkin. 2003. The Sea Urchin Embryo as a Model for Mammalian Developmental Neurotoxicity: Ontogenesis of the High-Affinity Choline Transporter and Its Role in Cholinergic Trophic Activity. Environmental Health Perspectives. 111(14):1730-1735.
Slotkin, Theodore. 2003. Guidelines for developmental neurotoxicity and their impact on organophosphate pesticides: a personal view from an academic perspective. NeuroToxicology. (in press)
Slotkin, Theodore. 2003. Serotonergic systems targeted by developmental exposure to chlorpyrifos: effects during different critical periods. Environmental Health Perspectives. 111:1736-1743.
Garcia, S.J., F.J. Seidler, D. Qiao, and Theodore Slotkin. 2002. Chlorpyrifos targets developing glia: effects on glial fibrillary acidic protein. Developmental Brain Research. 133(2):151-161.
Qiao, D., F.J. Seidler, S. Padilla, and Theodore Slotkin. 2002. Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period?. Environmental Health Perspectives. 110(11):1097-1103.
Slotkin, Theodore, C.A. Tate, M.M. Cousins, and F.J. Seidler. 2002. Functional alterations in CNS catecholamine systems in adolescence and adulthood after neonatal chlorpyrifos exposure. Developmental Brain Research. 133(2):163-173.
Yanai, J., O. Vatury, and Theodore Slotkin. 2002. Cell signaling as a target and underlying mechanism for neurobehavioral teratogenesis. Annals of the New York Academy of Science. 965:473-478.
Arthur, David and Edward Levin. 2001. Spatial and non-spatial visual discrimination learning in zebrafish (Danio rerio). Animal Cognition. 4:125-131.
Buznikov, G.A., V.V. Bezuglov, L.A. Nikitina, Theodore Slotkin, and J.M. Lauder. 2001. Cholinergic regulation of sea urchin embryonic and larval development. Russian Journal of Physiology. 87(11):1548-1556.
Buznikov, G.A., L.A. Nikitina, V.V. Bezuglov, J.M. Lauder, S. Padilla, and Theodore Slotkin. 2001. An invertebrate model of the developmental neurotoxicity of insecticides: effects of chlorpyrifos and dieldrin in sea urchin embryos and larvae. Environmental Health Perspectives. 109(7):651-661.
Garcia, S.J., F.J. Seidler, T.L. Crumpton, and Theodore Slotkin. 2001. Does the developmental neurotoxicity of chlorpyrifos involve glial targets? Macromolecule synthesis, adenylyl cyclase signaling, nuclear transcription factors, and formation of reactive oxygen in C6 glioma cells. Brain Research. 891(2):54-68.
Levin, Edward, N. Addy, A. Nakajima, N.C. Christopher, F.J. Seidler, and Theodore Slotkin. 2001. Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats. Developmental Brain Research. 130(1):83-89.
Navarro, H.A., P.V. Basta, F.J. Seidler, and Theodore Slotkin. 2001. Neonatal chlorpyrifos administration elicits deficits in immune function in adulthood: a neural effect?. Developmental Brain Research. 130(2):249-252.
Qiao, D., F.J. Seidler, and Theodore Slotkin. 2001. Developmental neurotoxicity of chlorpyrifos modeled in vitro: comparative effects of metabolites and other cholinesterase inhibitors on DNA synthesis in PC12 and C6 cells. Environmental Health Perspectives. 109(9):909-913.
Raines, K.W., F.J. Seidler, and Theodore Slotkin. 2001. Alterations in serotonin transporter expression in brain regions of rats exposed neonatally to chlorpyrifos. Developmental Brain Research. 130(1):65-72.
Slotkin, Theodore, M.M. Cousins, C.A. Tate, and F.J. Seidler. 2001. Persistent cholinergic presynaptic deficits after neonatal chlorpyrifos exposure. Brain Research. 902(2):229-243.
Auman, J.T., F.J. Seidler, and Theodore Slotkin. 2000. Neonatal chlorpyrifos exposure targets multiple proteins governing the hepatic adenylyl cyclase signaling cascade: implications for neurotoxicity. Developmental Brain Research. 121(1):19-27.
Crumpton, T.L., F.J. Seidler, and Theodore Slotkin. 2000. Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation. Brain Research. 857(2):80-98.
Crumpton, T.L., F.J. Seidler, and Theodore Slotkin. 2000. Is oxidative stress involved in the developmental neurotoxicity of chlorpyrifos?. Developmental Brain Research. 121(2):189-195.
Dam, K., F.J. Seidler, and Theodore Slotkin. 2000. Chlorpyrifos exposure during a critical neonatal period elicits gender-selective deficits in the development of coordination skills and locomotor activity. Developmental Brain Research. 121(2):179-187.