Is the PentaBDE replacement, tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a developmental neurotoxicant? Studies in PC12 cells.

Organophosphate flame retardants (OPFRs) are used as replacements for the commercial PentaBDE mixture that was phased out in 2004. OPFRs are ubiquitous in the environment and detected at high concentrations in residential dust, suggesting widespread human exposure. OPFRs are structurally similar to neurotoxic organophosphate pesticides, raising concerns about exposure and toxicity to humans. This study evaluated the neurotoxicity of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) compared to the organophosphate pesticide, chlorpyrifos (CPF), a known developmental neurotoxicant. We also tested the neurotoxicity of three structurally similar OPFRs, tris (2-chloroethyl) phosphate (TCEP), tris (1-chloropropyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP), and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a major component of PentaBDE. Using undifferentiated and differentiating PC12 cells, changes in DNA synthesis, oxidative stress, differentiation into dopaminergic or cholinergic neurophenotypes, cell number, cell growth and neurite growth were assessed. TDCPP displayed concentration-dependent neurotoxicity, often with effects equivalent to or greater than equimolar concentrations of CPF. TDCPP inhibited DNA synthesis, and all OPFRs decreased cell number and altered neurodifferentiation. Although TDCPP elevated oxidative stress, there was no adverse effect on cell viability or growth. TDCPP and TDBPP promoted differentiation into both neuronal phenotypes, while TCEP and TCPP promoted only the cholinergic phenotype. BDE-47 had no effect on cell number, cell growth or neurite growth. Our results demonstrate that different OPFRs show divergent effects on neurodifferentiation, suggesting the participation of multiple mechanisms of toxicity. Additionally, these data suggest that OPFRs may affect neurodevelopment with similar or greater potency compared to known and suspected neurotoxicants.

[1]  T. Slotkin,et al.  Chlorpyrifos Affects Phenotypic Outcomes in a Model of Mammalian Neurodevelopment: Critical Stages Targeting Differentiation in PC12 Cells , 2005, Environmental health perspectives.

[2]  S. Bondy,et al.  Developmental neurotoxicology , 2005, Journal of neuroscience research.

[3]  C. D. de Wit.  An overview of brominated flame retardants in the environment. , 2002, Chemosphere.

[4]  Anders Fredriksson,et al.  Neonatal exposure to higher brominated diphenyl ethers, hepta-, octa-, or nonabromodiphenyl ether, impairs spontaneous behavior and learning and memory functions of adult mice. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[5]  Eva Jakobsson,et al.  Neurobehavioral derangements in adult mice receiving decabrominated diphenyl ether (PBDE 209) during a defined period of neonatal brain development. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[6]  Peter Haglund,et al.  Organophosphorus flame retardants and plasticizers in air from various indoor environments. , 2005, Journal of environmental monitoring : JEM.

[7]  H. Anderson,et al.  Hormone Disruption by PBDEs in Adult Male Sport Fish Consumers , 2008, Environmental health perspectives.

[8]  M. Wullimann,et al.  Atlas of Early Zebrafish Brain Development: A Tool for Molecular Neurogenetics , 2005 .

[9]  M. van den Berg,et al.  Hydroxylation Increases the Neurotoxic Potential of BDE-47 to Affect Exocytosis and Calcium Homeostasis in PC12 Cells , 2008, Environmental health perspectives.

[10]  Ǻ. Bergman,et al.  An overview of commercially used brominated flame retardants, their applications, their use patterns in different countries/regions and possible modes of release. , 2003, Environment international.

[11]  Enrico Alleva,et al.  Effects of perinatal exposure to a polybrominated diphenyl ether (PBDE 99) on mouse neurobehavioural development. , 2002, Neurotoxicology.

[12]  Jorma Toppari,et al.  Flame Retardants in Placenta and Breast Milk and Cryptorchidism in Newborn Boys , 2007, Environmental health perspectives.

[13]  F. Berthou,et al.  Mammalian PC-12 cell genetically engineered for human cytochrome P450 2E1 expression. , 1993, European journal of biochemistry.

[14]  R. C. Dougherty,et al.  Tris(dichloropropyl)phosphate, a mutagenic flame retardant: frequent cocurrence in human seminal plasma. , 1981, Science.

[15]  Heather M Stapleton,et al.  Relationships between polybrominated diphenyl ether concentrations in house dust and serum. , 2010, Environmental science & technology.

[16]  T. Slotkin.  Developmental Neurotoxicity of Organophosphates: A Case Study of Chlorpyrifos , 2006 .

[17]  M. van den Berg,et al.  Neonatal Exposure to Brominated Flame Retardant BDE-47 Reduces Long-Term Potentiation and Postsynaptic Protein Levels in Mouse Hippocampus , 2007, Environmental health perspectives.

[18]  T. Reemtsma,et al.  Organophosphorus flame retardants and plasticizers in water and air II. Analytical methodology , 2008 .

[19]  Alex Tullo,et al.  Great Lakes To Phase Out Flame Retardants , 2003 .

[20]  Thorsten Reemtsma,et al.  Organophosphorus flame retardants and plasticizers in water and air I. Occurrence and fate , 2008 .

[21]  T. Suzuki,et al.  Hyperoxia induces the differentiated neuronal phenotype of PC12 cells by producing reactive oxygen species. , 1997, Biochemical and biophysical research communications.

[22]  J. Violin,et al.  Nicotine is a developmental neurotoxicant and neuroprotectant: stage-selective inhibition of DNA synthesis coincident with shielding from effects of chlorpyrifos. , 2003, Brain research. Developmental brain research.

[23]  J. Thome,et al.  Expression analyses of the mitochondrial complex I 75-kDa subunit in early onset schizophrenia and autism spectrum disorder: increased levels as a potential biomarker for early onset schizophrenia , 2010, European Child & Adolescent Psychiatry.

[24]  P. Haglund,et al.  Screening of organophosphorus compounds and their distribution in various indoor environments. , 2003, Chemosphere.

[25]  T. Slotkin,et al.  Screening for Developmental Neurotoxicity Using PC12 Cells: Comparisons of Organophosphates with a Carbamate, an Organochlorine, and Divalent Nickel , 2006, Environmental health perspectives.

[26]  J. Violin,et al.  Modeling the developmental neurotoxicity of chlorpyrifos in vitro: macromolecule synthesis in PC12 cells. , 1998, Toxicology and applied pharmacology.

[27]  F. Fumagalli,et al.  Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro , 2008, Brain Research Bulletin.

[28]  F. Fumagalli,et al.  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 , 2007, Environmental health perspectives.

[29]  Ming Wang,et al.  Effects of decabrominated diphenyl ether (PBDE 209) exposure at different developmental periods on synaptic plasticity in the dentate gyrus of adult rats In vivo. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[30]  L. Needham,et al.  Serum concentrations of polybrominated diphenyl ethers (PBDEs) and polybrominated biphenyl (PBB) in the United States population: 2003-2004. , 2008, Environmental science & technology.

[31]  J. Kennish,et al.  Disposition of the flame retardant, tris(1,3-dichloro-2-propyl) phosphate, in the rat. , 1981, Drug metabolism and disposition: the biological fate of chemicals.

[32]  Irva Hertz-Picciotto,et al.  PBDEs in 2-5 year-old children from California and associations with diet and indoor environment. , 2010, Environmental science & technology.

[33]  Paavo Honkakoski,et al.  Effects of triaryl phosphates on mouse and human nuclear receptors. , 2004, Biochemical pharmacology.

[34]  Asa Bradman,et al.  PBDE Concentrations in Women’s Serum and Fecundability , 2010, Environmental health perspectives.

[35]  H. Stapleton,et al.  Serum levels of polybrominated diphenyl ethers (PBDEs) in foam recyclers and carpet installers working in the United States. , 2008, Environmental science & technology.

[36]  Shin-ichi Sakai,et al.  Flame retardants in indoor dust and air of a hotel in Japan. , 2009, Environment international.

[37]  N. Koibuchi,et al.  Increase in Cerebellar Neurotrophin-3 and Oxidative Stress Markers in Autism , 2009, The Cerebellum.

[38]  C. Carter,et al.  Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability , 2006, Schizophrenia Research.

[39]  Deliang Tang,et al.  Prenatal Exposure to PBDEs and Neurodevelopment , 2010, Environmental health perspectives.

[40]  M. van den Berg,et al.  Calcium-related processes involved in the inhibition of depolarization-evoked calcium increase by hydroxylated PBDEs in PC12 cells. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[41]  J. Meeker,et al.  Detection of organophosphate flame retardants in furniture foam and U.S. house dust. , 2009, Environmental science & technology.

[42]  A. E. Ahmed,et al.  Whole‐body autoradiographic disposition, elimination and placental transport of [14C]Tri‐o‐cresyl phosphate in mice , 1993, Journal of applied toxicology : JAT.

[43]  M. van den Berg,et al.  Bromination Pattern of Hydroxylated Metabolites of BDE-47 Affects Their Potency to Release Calcium from Intracellular Stores in PC12 Cells , 2009, Environmental health perspectives.

[44]  B. Ames,et al.  Flame-retardant additives as possible cancer hazards. , 1977, Science.

[45]  R. Letcher,et al.  Metabolism of Polybrominated Diphenyl Ethers (PBDEs) by Human Hepatocytes in Vitro , 2008, Environmental health perspectives.

[46]  T. Poet,et al.  In vitro rat hepatic and intestinal metabolism of the organophosphate pesticides chlorpyrifos and diazinon. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[47]  Heather M Stapleton,et al.  Polybrominated diphenyl ether flame retardants in the North American environment. , 2003, Environment international.

[48]  C. Pope.  Organophosphorus pesticides: do they all have the same mechanism of toxicity? , 1999, Journal of toxicology and environmental health. Part B, Critical reviews.

[49]  John D Meeker,et al.  Polybrominated diphenyl ether (PBDE) concentrations in house dust are related to hormone levels in men. , 2009, The Science of the total environment.

[50]  T. Slotkin,et al.  Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos. , 2005, Toxicology and applied pharmacology.

[51]  Matthew Lorber,et al.  Exposure of Americans to polybrominated diphenyl ethers , 2008, Journal of Exposure Science and Environmental Epidemiology.

[52]  R. Letcher,et al.  Dietary accumulation and metabolism of polybrominated diphenyl ethers by juvenile carp (Cyprinus carpio) , 2004, Environmental toxicology and chemistry.

[53]  Heather M. Stapleton,et al.  Alternate and new brominated flame retardants detected in U.S. house dust. , 2008 .

[54]  L. Costa,et al.  Measurement of paraoxonase (PON1) status as a potential biomarker of susceptibility to organophosphate toxicity. , 2005, Clinica chimica acta; international journal of clinical chemistry.

[55]  Daniel Cerutti,et al.  Zebrafish provide a sensitive model of persisting neurobehavioral effects of developmental chlorpyrifos exposure: comparison with nicotine and pilocarpine effects and relationship to dopamine deficits. , 2010, Neurotoxicology and teratology.

[56]  Olaf Päpke,et al.  Levels of polybrominated diphenyl ethers (PBDEs) in breast milk from central Taiwan and their relation to infant birth outcome and maternal menstruation effects. , 2007, Environment international.

[57]  B. Ross,et al.  Increased Levels of Ethane, A Non-invasive Marker of n-3 Fatty Acid Oxidation, in Breath of Children with Attention Deficit Hyperactivity Disorder , 2003, Nutritional neuroscience.

[58]  John D. Meeker,et al.  House Dust Concentrations of Organophosphate Flame Retardants in Relation to Hormone Levels and Semen Quality Parameters , 2009, Environmental health perspectives.

[59]  G. Marsh,et al.  Identification of hydroxylated metabolites in 2,2',4,4'-tetrabromodiphenyl ether exposed rats. , 2006, Chemosphere.

[60]  L. Nadel,et al.  Review of the Toxicology of Chlorpyrifos With an Emphasis on Human Exposure and Neurodevelopment , 2008 .

[61]  G. M. Richardson,et al.  Is house dust the missing exposure pathway for PBDEs? An analysis of the urban fate and human exposure to PBDEs. , 2005, Environmental science & technology.

[62]  David T. Williams,et al.  Triaryl/alkyl phosphate residues in human adipose autopsy samples from six ontario municipalities , 1989, Bulletin of environmental contamination and toxicology.

[63]  H. Navarro,et al.  Nutritional Influences on Adrenal Chromaffin Cell Development: Comparison with Central Neurons , 1988, Pediatric Research.

[64]  Michael Berk,et al.  Neurobiology of schizophrenia spectrum disorders: the role of oxidative stress. , 2009, Annals of the Academy of Medicine, Singapore.

[65]  Åke Bergman,et al.  Children Show Highest Levels of Polybrominated Diphenyl Ethers in a California Family of Four: A Case Study , 2006, Environmental health perspectives.

[66]  Donald G Patterson,et al.  A review on human exposure to brominated flame retardants--particularly polybrominated diphenyl ethers. , 2003, Environment international.

[67]  T. Slotkin,et al.  Developmental neurotoxicity of chlorpyrifos modeled in vitro: comparative effects of metabolites and other cholinesterase inhibitors on DNA synthesis in PC12 and C6 cells. , 2001, Environmental health perspectives.

[68]  R. Hites,et al.  Measurement of Polybrominated Diphenyl Ethers and Metabolites in Mouse Plasma after Exposure to a Commercial Pentabromodiphenyl Ether Mixture , 2007, Environmental health perspectives.

[69]  R N Stillwell,et al.  Children absorb tris-BP flame retardant from sleepwear: urine contains the mutagenic metabolite, 2,3-dibromopropanol. , 1978, Science.

[70]  Peter Haglund,et al.  Organophosphorus flame retardants and plasticizers in Swedish sewage treatment plants. , 2005, Environmental science & technology.

[71]  M. D. Gold,et al.  Another flame retardant, tris-(1,3-dichloro-2-propyl)-phosphate, and its expected metabolites are mutagens. , 1978, Science.