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Whole genome microarray analysis of neural progenitor C17.2 cells during differentiation and validation of 30 neural mRNA biomarkers for estimation of developmental neurotoxicity.

Abstract Despite its high relevance, developmental neurotoxicity (DNT) is one of the least studied forms of toxicity. Current guidelines for DNT testing are based on in vivo testing and they require extensive resources. Transcriptomic approaches using relevant in vitro models have been suggested as a useful tool for identifying possible DNT-generating compounds. In this study, we performed whole genome microarray analysis on the murine progenitor cell line C17.2 following 5 and 10 days of differentiation. We identified 30 genes that are strongly associated with neural differentiation. The C17.2 cell line can be differentiated into a co-culture of both neurons and neuroglial cells, giving a more relevant picture of the brain than using neuronal cells alone. Among the most highly upregulated genes were genes involved in neurogenesis (CHRDL1), axonal guidance (BMP4), neuronal connectivity (PLXDC2), axonogenesis (RTN4R) and astrocyte differentiation (S100B). The 30 biomarkers were further validated by exposure to non-cytotoxic concentrations of two DNT-inducing compounds (valproic acid and methylmercury) and one neurotoxic chemical possessing a possible DNT activity (acrylamide). Twenty-eight of the 30 biomarkers were altered by at least one of the neurotoxic substances, proving the importance of these biomarkers during differentiation. These results suggest that gene expression profiling using a predefined set of biomarkers could be used as a sensitive tool for initial DNT screening of chemicals. Using a predefined set of mRNA biomarkers, instead of the whole genome, makes this model affordable and high-throughput. The use of such models could help speed up the initial screening of substances, possibly indicating alerts that need to be further studied in more sophisticated models.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 29261810
OWN - NLM
STAT- In-Process
LR  - 20171220
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 12
DP  - 2017
TI  - Whole genome microarray analysis of neural progenitor C17.2 cells during
      differentiation and validation of 30 neural mRNA biomarkers for estimation of
      developmental neurotoxicity.
PG  - e0190066
LID - 10.1371/journal.pone.0190066 [doi]
AB  - Despite its high relevance, developmental neurotoxicity (DNT) is one of the least
      studied forms of toxicity. Current guidelines for DNT testing are based on in
      vivo testing and they require extensive resources. Transcriptomic approaches
      using relevant in vitro models have been suggested as a useful tool for
      identifying possible DNT-generating compounds. In this study, we performed whole 
      genome microarray analysis on the murine progenitor cell line C17.2 following 5
      and 10 days of differentiation. We identified 30 genes that are strongly
      associated with neural differentiation. The C17.2 cell line can be differentiated
      into a co-culture of both neurons and neuroglial cells, giving a more relevant
      picture of the brain than using neuronal cells alone. Among the most highly
      upregulated genes were genes involved in neurogenesis (CHRDL1), axonal guidance
      (BMP4), neuronal connectivity (PLXDC2), axonogenesis (RTN4R) and astrocyte
      differentiation (S100B). The 30 biomarkers were further validated by exposure to 
      non-cytotoxic concentrations of two DNT-inducing compounds (valproic acid and
      methylmercury) and one neurotoxic chemical possessing a possible DNT activity
      (acrylamide). Twenty-eight of the 30 biomarkers were altered by at least one of
      the neurotoxic substances, proving the importance of these biomarkers during
      differentiation. These results suggest that gene expression profiling using a
      predefined set of biomarkers could be used as a sensitive tool for initial DNT
      screening of chemicals. Using a predefined set of mRNA biomarkers, instead of the
      whole genome, makes this model affordable and high-throughput. The use of such
      models could help speed up the initial screening of substances, possibly
      indicating alerts that need to be further studied in more sophisticated models.
FAU - Attoff, Kristina
AU  - Attoff K
AUID- ORCID: http://orcid.org/0000-0002-6611-0785
AD  - Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
FAU - Gliga, Anda
AU  - Gliga A
AD  - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
FAU - Lundqvist, Jessica
AU  - Lundqvist J
AD  - Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
AD  - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Sodertalje, Sweden.
FAU - Norinder, Ulf
AU  - Norinder U
AD  - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Sodertalje, Sweden.
FAU - Forsby, Anna
AU  - Forsby A
AD  - Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
AD  - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Sodertalje, Sweden.
LA  - eng
PT  - Journal Article
DEP - 20171220
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
EDAT- 2017/12/21 06:00
MHDA- 2017/12/21 06:00
CRDT- 2017/12/21 06:00
PHST- 2017/09/20 00:00 [received]
PHST- 2017/12/07 00:00 [accepted]
PHST- 2017/12/21 06:00 [entrez]
PHST- 2017/12/21 06:00 [pubmed]
PHST- 2017/12/21 06:00 [medline]
AID - 10.1371/journal.pone.0190066 [doi]
AID - PONE-D-17-34169 [pii]
PST - epublish
SO  - PLoS One. 2017 Dec 20;12(12):e0190066. doi: 10.1371/journal.pone.0190066.
      eCollection 2017.