Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Kelly Burke, Yinghong Cheng, Baogang Li, Alex Petrov, Pushkar Joshi, Robert F Berman, Kenneth R. Reuhl, Emanuel DiCicco-Bloom

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

The developing brain is highly sensitive to methylmercury (MeHg). Still, the initial changes in cell proliferation that may contribute to long-term MeHg effects are largely undefined. Our previous studies with growth factors indicate that acute alterations of the G1/S-phase transition can permanently affect cell numbers and organ size. Therefore, we determined whether an environmental toxicant could also impact brain development with rapid (6-7 h) effects on DNA synthesis and cell cycle machinery in neuronal precursors. In vivo studies in newborn rat hippocampus and cerebellum, two regions of postnatal neurogenesis, were followed by in vitro analysis of two precursor models, cortical and cerebellar cells, focusing on the proteins that regulate the G1/S transition. In postnatal day 7 (P7) pups, a single subcutaneous injection of MeHg (3 μg/g) acutely (7 h) decreased DNA synthesis in the hippocampus by 40% and produced long-term (2 weeks) reductions in total cell number, estimated by DNA quantification. Surprisingly, cerebellar granule cells were resistant to MeHg effects in vivo at comparable tissue concentrations, suggesting region-specific differences in precursor populations. In vitro, MeHg altered proliferation and cell viability, with DNA synthesis selectively inhibited at an early timepoint (6 h) corresponding to our in vivo observations. Considering that G1/S regulators are targets of exogenous signals, we used a well-defined cortical cell model to examine MeHg effects on relevant cyclin-dependent kinases (CDK) and CDK inhibitors. At 6 h, MeHg decreased by 75% levels of cyclin E, a cell cycle regulator with roles in proliferation and apoptosis, without altering p57, p27, or CDK2 nor levels of activated caspase 3. In aggregate, our observations identify the G1/S transition as an early target of MeHg toxicity and raise the possibility that cyclin E degradation contributes to both decreased proliferation and eventual cell death.

Original languageEnglish (US)
Pages (from-to)970-981
Number of pages12
JournalNeuroToxicology
Volume27
Issue number6
DOIs
StatePublished - Dec 2006

Fingerprint

Cyclin E
Cell proliferation
Brain
Cell Cycle
Cells
Cell Proliferation
Cyclin-Dependent Kinases
DNA
Hippocampus
Cell Count
Organ Size
Phase Transition
Neurogenesis
G1 Phase
Cell death
Subcutaneous Injections
S Phase
Cell Size
Caspase 3
Cerebellum

Keywords

  • Cell cycle
  • Cell survival
  • Cerebellar granule precursors
  • Cerebral cortex
  • Cyclin E
  • Hippocampus
  • Mercury
  • Neural stem cell
  • Neurogenesis
  • Proliferation

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neuroscience(all)
  • Toxicology

Cite this

Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E. / Burke, Kelly; Cheng, Yinghong; Li, Baogang; Petrov, Alex; Joshi, Pushkar; Berman, Robert F; Reuhl, Kenneth R.; DiCicco-Bloom, Emanuel.

In: NeuroToxicology, Vol. 27, No. 6, 12.2006, p. 970-981.

Research output: Contribution to journalArticle

Burke, Kelly ; Cheng, Yinghong ; Li, Baogang ; Petrov, Alex ; Joshi, Pushkar ; Berman, Robert F ; Reuhl, Kenneth R. ; DiCicco-Bloom, Emanuel. / Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E. In: NeuroToxicology. 2006 ; Vol. 27, No. 6. pp. 970-981.
@article{25dde447bcd54ac7ae71ca530bdea734,
title = "Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E",
abstract = "The developing brain is highly sensitive to methylmercury (MeHg). Still, the initial changes in cell proliferation that may contribute to long-term MeHg effects are largely undefined. Our previous studies with growth factors indicate that acute alterations of the G1/S-phase transition can permanently affect cell numbers and organ size. Therefore, we determined whether an environmental toxicant could also impact brain development with rapid (6-7 h) effects on DNA synthesis and cell cycle machinery in neuronal precursors. In vivo studies in newborn rat hippocampus and cerebellum, two regions of postnatal neurogenesis, were followed by in vitro analysis of two precursor models, cortical and cerebellar cells, focusing on the proteins that regulate the G1/S transition. In postnatal day 7 (P7) pups, a single subcutaneous injection of MeHg (3 μg/g) acutely (7 h) decreased DNA synthesis in the hippocampus by 40{\%} and produced long-term (2 weeks) reductions in total cell number, estimated by DNA quantification. Surprisingly, cerebellar granule cells were resistant to MeHg effects in vivo at comparable tissue concentrations, suggesting region-specific differences in precursor populations. In vitro, MeHg altered proliferation and cell viability, with DNA synthesis selectively inhibited at an early timepoint (6 h) corresponding to our in vivo observations. Considering that G1/S regulators are targets of exogenous signals, we used a well-defined cortical cell model to examine MeHg effects on relevant cyclin-dependent kinases (CDK) and CDK inhibitors. At 6 h, MeHg decreased by 75{\%} levels of cyclin E, a cell cycle regulator with roles in proliferation and apoptosis, without altering p57, p27, or CDK2 nor levels of activated caspase 3. In aggregate, our observations identify the G1/S transition as an early target of MeHg toxicity and raise the possibility that cyclin E degradation contributes to both decreased proliferation and eventual cell death.",
keywords = "Cell cycle, Cell survival, Cerebellar granule precursors, Cerebral cortex, Cyclin E, Hippocampus, Mercury, Neural stem cell, Neurogenesis, Proliferation",
author = "Kelly Burke and Yinghong Cheng and Baogang Li and Alex Petrov and Pushkar Joshi and Berman, {Robert F} and Reuhl, {Kenneth R.} and Emanuel DiCicco-Bloom",
year = "2006",
month = "12",
doi = "10.1016/j.neuro.2006.09.001",
language = "English (US)",
volume = "27",
pages = "970--981",
journal = "NeuroToxicology",
issn = "0161-813X",
publisher = "Elsevier",
number = "6",

}

TY - JOUR

T1 - Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

AU - Burke, Kelly

AU - Cheng, Yinghong

AU - Li, Baogang

AU - Petrov, Alex

AU - Joshi, Pushkar

AU - Berman, Robert F

AU - Reuhl, Kenneth R.

AU - DiCicco-Bloom, Emanuel

PY - 2006/12

Y1 - 2006/12

N2 - The developing brain is highly sensitive to methylmercury (MeHg). Still, the initial changes in cell proliferation that may contribute to long-term MeHg effects are largely undefined. Our previous studies with growth factors indicate that acute alterations of the G1/S-phase transition can permanently affect cell numbers and organ size. Therefore, we determined whether an environmental toxicant could also impact brain development with rapid (6-7 h) effects on DNA synthesis and cell cycle machinery in neuronal precursors. In vivo studies in newborn rat hippocampus and cerebellum, two regions of postnatal neurogenesis, were followed by in vitro analysis of two precursor models, cortical and cerebellar cells, focusing on the proteins that regulate the G1/S transition. In postnatal day 7 (P7) pups, a single subcutaneous injection of MeHg (3 μg/g) acutely (7 h) decreased DNA synthesis in the hippocampus by 40% and produced long-term (2 weeks) reductions in total cell number, estimated by DNA quantification. Surprisingly, cerebellar granule cells were resistant to MeHg effects in vivo at comparable tissue concentrations, suggesting region-specific differences in precursor populations. In vitro, MeHg altered proliferation and cell viability, with DNA synthesis selectively inhibited at an early timepoint (6 h) corresponding to our in vivo observations. Considering that G1/S regulators are targets of exogenous signals, we used a well-defined cortical cell model to examine MeHg effects on relevant cyclin-dependent kinases (CDK) and CDK inhibitors. At 6 h, MeHg decreased by 75% levels of cyclin E, a cell cycle regulator with roles in proliferation and apoptosis, without altering p57, p27, or CDK2 nor levels of activated caspase 3. In aggregate, our observations identify the G1/S transition as an early target of MeHg toxicity and raise the possibility that cyclin E degradation contributes to both decreased proliferation and eventual cell death.

AB - The developing brain is highly sensitive to methylmercury (MeHg). Still, the initial changes in cell proliferation that may contribute to long-term MeHg effects are largely undefined. Our previous studies with growth factors indicate that acute alterations of the G1/S-phase transition can permanently affect cell numbers and organ size. Therefore, we determined whether an environmental toxicant could also impact brain development with rapid (6-7 h) effects on DNA synthesis and cell cycle machinery in neuronal precursors. In vivo studies in newborn rat hippocampus and cerebellum, two regions of postnatal neurogenesis, were followed by in vitro analysis of two precursor models, cortical and cerebellar cells, focusing on the proteins that regulate the G1/S transition. In postnatal day 7 (P7) pups, a single subcutaneous injection of MeHg (3 μg/g) acutely (7 h) decreased DNA synthesis in the hippocampus by 40% and produced long-term (2 weeks) reductions in total cell number, estimated by DNA quantification. Surprisingly, cerebellar granule cells were resistant to MeHg effects in vivo at comparable tissue concentrations, suggesting region-specific differences in precursor populations. In vitro, MeHg altered proliferation and cell viability, with DNA synthesis selectively inhibited at an early timepoint (6 h) corresponding to our in vivo observations. Considering that G1/S regulators are targets of exogenous signals, we used a well-defined cortical cell model to examine MeHg effects on relevant cyclin-dependent kinases (CDK) and CDK inhibitors. At 6 h, MeHg decreased by 75% levels of cyclin E, a cell cycle regulator with roles in proliferation and apoptosis, without altering p57, p27, or CDK2 nor levels of activated caspase 3. In aggregate, our observations identify the G1/S transition as an early target of MeHg toxicity and raise the possibility that cyclin E degradation contributes to both decreased proliferation and eventual cell death.

KW - Cell cycle

KW - Cell survival

KW - Cerebellar granule precursors

KW - Cerebral cortex

KW - Cyclin E

KW - Hippocampus

KW - Mercury

KW - Neural stem cell

KW - Neurogenesis

KW - Proliferation

UR - http://www.scopus.com/inward/record.url?scp=33751508327&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33751508327&partnerID=8YFLogxK

U2 - 10.1016/j.neuro.2006.09.001

DO - 10.1016/j.neuro.2006.09.001

M3 - Article

C2 - 17056119

AN - SCOPUS:33751508327

VL - 27

SP - 970

EP - 981

JO - NeuroToxicology

JF - NeuroToxicology

SN - 0161-813X

IS - 6

ER -