Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex

Henrik Alm, Kim Kultima, Birger Scholz, Anna Nilsson, Per E Andrén, Åsa Fex Svenningsen, Lennart Dencker, Michael Stigson

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29%) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.
Original languageEnglish
JournalNeuroToxicology
Volume29
Issue number4
Pages (from-to)628-37
Number of pages9
ISSN0161-813X
DOIs
Publication statusPublished - 2008

Fingerprint

Halogenated Diphenyl Ethers
Flame Retardants
Cytoskeletal Proteins
Two-Dimensional Difference Gel Electrophoresis
Proteins
Caspase 3
Brain
Trypan Blue
Cell death
Fractionation
Growth
Electrophoresis
Neurons
Rats
Cultured Cells
Assays
Cell Survival
Animals
Cell Death
Gels

Keywords

  • Animals
  • Animals, Newborn
  • Apoptosis
  • Caspase 3
  • Cell Membrane
  • Cells, Cultured
  • Cerebral Cortex
  • Cytoskeletal Proteins
  • Cytosol
  • Dose-Response Relationship, Drug
  • Electrophoresis, Gel, Two-Dimensional
  • Embryo, Mammalian
  • Female
  • Flame Retardants
  • Gene Expression Regulation
  • Halogenated Diphenyl Ethers
  • Mice
  • Neurons
  • Phenyl Ethers
  • Polybrominated Biphenyls
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley

Cite this

Alm, Henrik ; Kultima, Kim ; Scholz, Birger ; Nilsson, Anna ; Andrén, Per E ; Svenningsen, Åsa Fex ; Dencker, Lennart ; Stigson, Michael. / Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex. In: NeuroToxicology. 2008 ; Vol. 29, No. 4. pp. 628-37.
@article{99f19360fa0511deaefb000ea68e967b,
title = "Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex",
abstract = "Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29{\%}) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.",
keywords = "Animals, Animals, Newborn, Apoptosis, Caspase 3, Cell Membrane, Cells, Cultured, Cerebral Cortex, Cytoskeletal Proteins, Cytosol, Dose-Response Relationship, Drug, Electrophoresis, Gel, Two-Dimensional, Embryo, Mammalian, Female, Flame Retardants, Gene Expression Regulation, Halogenated Diphenyl Ethers, Mice, Neurons, Phenyl Ethers, Polybrominated Biphenyls, Pregnancy, Rats, Rats, Sprague-Dawley",
author = "Henrik Alm and Kim Kultima and Birger Scholz and Anna Nilsson and Andr{\'e}n, {Per E} and Svenningsen, {{\AA}sa Fex} and Lennart Dencker and Michael Stigson",
year = "2008",
doi = "10.1016/j.neuro.2008.04.021",
language = "English",
volume = "29",
pages = "628--37",
journal = "NeuroToxicology",
issn = "0161-813X",
publisher = "Elsevier",
number = "4",

}

Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex. / Alm, Henrik; Kultima, Kim; Scholz, Birger; Nilsson, Anna; Andrén, Per E; Svenningsen, Åsa Fex; Dencker, Lennart; Stigson, Michael.

In: NeuroToxicology, Vol. 29, No. 4, 2008, p. 628-37.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex

AU - Alm, Henrik

AU - Kultima, Kim

AU - Scholz, Birger

AU - Nilsson, Anna

AU - Andrén, Per E

AU - Svenningsen, Åsa Fex

AU - Dencker, Lennart

AU - Stigson, Michael

PY - 2008

Y1 - 2008

N2 - Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29%) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.

AB - Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29%) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.

KW - Animals

KW - Animals, Newborn

KW - Apoptosis

KW - Caspase 3

KW - Cell Membrane

KW - Cells, Cultured

KW - Cerebral Cortex

KW - Cytoskeletal Proteins

KW - Cytosol

KW - Dose-Response Relationship, Drug

KW - Electrophoresis, Gel, Two-Dimensional

KW - Embryo, Mammalian

KW - Female

KW - Flame Retardants

KW - Gene Expression Regulation

KW - Halogenated Diphenyl Ethers

KW - Mice

KW - Neurons

KW - Phenyl Ethers

KW - Polybrominated Biphenyls

KW - Pregnancy

KW - Rats

KW - Rats, Sprague-Dawley

U2 - 10.1016/j.neuro.2008.04.021

DO - 10.1016/j.neuro.2008.04.021

M3 - Journal article

VL - 29

SP - 628

EP - 637

JO - NeuroToxicology

JF - NeuroToxicology

SN - 0161-813X

IS - 4

ER -